Pyrrolidine gpr40 modulators

ABSTRACT

The present invention provides compounds of Formula (I): or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser. No. 61/989,601, filed May 7, 2014, the entire content of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides novel carboxylic acid substituted pyrrolidine compounds, and their analogues thereof, which are GPR40 G protein-coupled receptor modulators, compositions containing them, and methods of using them, for example, for the treatment of diabetes and related conditions.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a progressively debilitating disorder of epidemic proportions leading to various micro- and macrovascular complications and morbidity. The most common type of diabetes, type 2 diabetes, is characterized by increasing insulin resistance associated with inadequate insulin secretion after a period of compensatory hyperinsulinemia. Free fatty acids (FFAs) are evidenced to influence insulin secretion from β cells primarily by enhancing glucose-stimulated insulin secretion (GSIS). G-protein coupled receptors (GPCRs) expressed in β cells are known to modulate the release of insulin in response to changes in plasma glucose levels. GPR40, also known as fatty acid receptor 1 (FFAR1), is a membrane-bound FFA receptor which is preferentially expressed in the pancreatic islets and specifically in β cells and mediates medium to long chain fatty acid induced insulin secretion. GPR40 is also expressed in enteroendocrine cells wherein activation promotes the secretion of gut incretin hormones, such as GLP-1, GIP, CCK and PYY. To decrease medical burden of type 2 diabetes through enhanced glycemic control, GPR40 modulator compounds hold the promise of exerting an incretin effect to promote GSIS as well as potential combination with a broad range of anti-diabetic drugs.

The present invention relates to novel substituted pyrrolidine compounds which have the ability to modulate GPR40. Such compounds are therefore potentially useful for the treatment of diabetes and related conditions.

SUMMARY OF THE INVENTION

The present invention provides substituted pyrrolidine compounds, and their analogues thereof, which are useful as GPR40 modulators, including stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, or solvates thereof.

The present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, or solvates thereof.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, or solvates thereof.

The present invention also provides a crystalline form of one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts, polymorphs, or solvates thereof.

The compounds of the invention may be used in the treatment of multiple diseases or disorders associated with GPR40, such as diabetes and related conditions, microvascular complications associated with diabetes, the macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, disorders of glucose metabolism, obesity and other maladies.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of a medicament for the treatment of multiple diseases or disorders associated with GPR40.

The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more other agent(s).

Other features and advantages of the invention will be apparent from the following detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present disclosure provides, inter alia, a compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:

ring A is independently

ring B is independently a 6-membered aryl or 5- to 6-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, O, and S; and ring B is substituted with 0-4 R²;

R¹ is independently phenyl, benzyl, naphthyl or a 5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said phenyl, benzyl, naphthyl and heteroaryl are each substituted with 0-3 R⁶;

R², at each occurrence, is independently selected from: ═O, OH, halogen, C₁₋₆ alkyl substituted with 0-1 R¹², C₁₋₆ alkoxy substituted with 0-1 R¹², C₁₋₄ haloalkyl substituted with 0-1 R¹², C₁₋₄ haloalkoxy substituted with 0-1 R¹², —(CH₂)_(m)—C₃₋₆ carbocycle substituted with 0-1 R¹², and —(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S); wherein said heteroaryl is substituted with 0-1 R¹²;

R³ is independently selected from: CN, C₁₋₆ alkyl substituted with 1 R¹⁶, C₁₋₆ alkoxy substituted with 1 R¹⁶, C₂₋₆ alkenyl substituted with 0-1 R¹⁶, C₂₋₆ alkynyl substituted with 0-1 R¹⁶, C₁₋₆ haloalkyl substituted with 1 R¹⁶, —(O)_(n)—(CH₂)_(m)—(C₃₋₆ carbocycle substituted with 0-2 R¹⁰), —(O)_(n)—(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said heteroaryl is substituted with 0-2 R¹⁰);

R⁴ and R^(4a) are independently selected from: H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —(CH₂)_(m)—C₃₋₆ carbocycle;

R⁵, at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy;

R⁶, at each occurrence, is independently selected from: halogen, OH, C₁₋₄ alkylthio, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₈ alkyl substituted with 0-1 R⁷, C₁₋₆ alkoxy substituted with 0-1 R⁷, —(O)_(n)—(CH₂)_(m)—(C₃₋₁₀ carbocycle substituted with 0-2 R⁷), and —(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S); wherein said heteroaryl is substituted with 0-2 R⁷;

R⁷, at each occurrence, is independently selected from: halogen, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, SCF₃, CN, NO₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SO₂(C₁₋₂ alkyl), and phenyl;

R⁸ is independently selected from: H and C₁₋₄ alkyl;

R¹⁰ and R¹², at each occurrence, is independently selected from: OH, halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), and tetrazolyl;

R¹¹, at each occurrence, is independently selected from: H, C₁₋₄ alkyl and benzyl;

m, at each occurrence, is independently 0, 1, or 2; and

n, at each occurrence, is independently 0 or 1.

In a second aspect, the present disclosure provides a compound of Formula (I), wherein R⁴ is hydrogen and R⁸ is hydrogen, further characterized by Formula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:

ring A is independently

ring B is independently

R¹ is independently phenyl, benzyl, naphthyl or a 5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said phenyl, benzyl, naphthyl and heteroaryl are each substituted with 0-3 R⁶;

R², at each occurrence, is independently selected from: ═O, OH, halogen, C₁₋₆ alkyl substituted with 0-1 R¹², C₁₋₆ alkoxy substituted with 0-1 R¹², C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and benzyl;

R³ is independently selected from: CN, C₁₋₆ alkyl substituted with 1 R¹⁰, C₁₋₆ alkoxy substituted with 1 R¹⁰, —(O)_(n)—(CH₂)_(m)—(C₃₋₆ cycloalkyl substituted with 0-2 R¹⁰), —(O)_(n)—(CH₂)_(m)-(phenyl substituted with 0-2 R¹⁰), and —(O)_(n)—(CH₂)_(m)-(a 5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said heteroaryl is substituted with 0-2 R¹⁰);

R^(4a) is independently selected from: H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, and —(CH₂)_(m)—C₃₋₆ carbocycle;

R⁵, at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy;

R⁶, at each occurrence, is independently selected from: halogen, OH, C₁₋₄ alkylthio, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₈ alkyl substituted with 0-1 R⁷, C₁₋₄ alkoxy substituted with 0-1 R⁷, —(O)_(n)—(CH₂)_(m)—(C₃₋₆ carbocycle substituted with 0-2 R⁷), —(CH₂)_(m)-(naphthyl substituted with 0-2 R⁷), and —(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said heteroaryl is substituted with 0-2 R⁷);

R⁷, at each occurrence, is independently selected from: halogen, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, SCF₃, CN, NO₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SO₂(C₁₋₂ alkyl), and phenyl;

R¹⁰ and R¹², at each occurrence, are independently selected from: OH, halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), and tetrazolyl;

R¹¹, at each occurrence, is independently selected from: H, C₁₋₄ alkyl and benzyl;

m, at each occurrence, is independently 0, 1, or 2; and

n, at each occurrence, is independently 0 or 1.

In a third aspect, the present disclosure includes a compound of Formula (I) or (II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, within the scope of the first or second aspect, wherein:

ring A is independently

R¹ is independently phenyl substituted with 0-3 R⁶ or a heteroaryl substituted with 0-2 R⁶; wherein said heteroaryl is selected from: furanyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl;

R², at each occurrence, is independently selected from: OH, halogen, C₁₋₄ alkyl substituted with 0-1 R¹², C₁₋₄ alkoxy substituted with 0-1 R¹², and benzyl;

R^(4a) is independently selected from: H, halogen C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₃₋₆ cycloalkyl;

R⁶, at each occurrence, is independently selected from: halogen, OH, C₁₋₈ alkyl substituted with 0-1 OH, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄ alkyl, C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl, —O—C₃₋₆ cycloalkyl, benzyl, and oxazolyl; and

R¹⁰ and R¹², at each occurrence, are independently selected from: halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, SO₂(C₁₋₄ alkyl), and CO₂(C₁₋₂ alkyl), and tetrazolyl.

In a fourth aspect, the present invention includes a compound of Formula (I) or (II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, within the scope of the first, second or third aspect, wherein:

R¹ is independently phenyl substituted with 0-3 R⁶ or a heteroaryl substituted with 0-2 R⁶; wherein said heteroaryl is selected from: thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl.

In a fifth aspect, the present disclosure includes a compound of Formula (I) or (II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, within the scope of any of the above aspect, wherein:

R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶, pyridinyl substituted with 0-2 R⁶, pyrazinyl substituted with 0-2 R⁶, pyrimidinyl substituted with 0-2 R⁶, or thiazolyl substituted with 0-2 R⁶;

R², at each occurrence, is independently selected from: OH, halogen, C₁₋₆ alkyl substituted with 0-1 CN, C₁₋₆ alkoxy, benzyl, and tetrazolylmethyl;

R⁶, at each occurrence, is independently selected from: halogen, CN, C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄ alkyl, C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl, —O—C₃₋₆ cycloalkyl, benzyl, and oxazolyl; and

R¹⁰, at each occurrence, is independently selected from: halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and CO₂(C₁₋₂ alkyl).

In a sixth aspect, the present disclosure includes a compound of Formula (I) or (II), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, within the scope of any of the above aspect, wherein:

R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶ or pyridinyl substituted with 0-2 R⁶;

R², at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy;

R³ is independently selected from: CN, C₁₋₆ alkyl substituted with 1 R¹⁰, C₁₋₆ alkoxy substituted with 1 R¹⁰, —(O)_(n)—(CH₂)_(m)—(C₃₋₆ cycloalkyl substituted with 0-1 R¹⁰), —(O)_(n)—(CH₂)_(m)-(phenyl substituted with 0-2 R¹⁰), and —(O)_(n)—(CH₂)_(m)-(a 5- to 6-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said heteroaryl is substituted with 0-1 R¹⁰);

R⁶, at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄ alkyl, C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl, and benzyl; and

R¹⁰, at each occurrence, is independently selected from: halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, and C₁₋₄ haloalkoxy.

In a seventh aspect, the present disclosure includes a compound of Formula (III) or (IIIA):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:

R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶ or pyridinyl substituted with 0-2 R⁶;

R², at each occurrence, is independently selected from: halogen, C₁₋₄ alkyl, and C₁₋₆ alkoxy;

R³, at each occurrence, is independently selected from: CN, C₁₋₄ alkoxy substituted with 1 R¹⁰, —(CH₂)_(m)—(C₃₋₆ cycloalkyl substituted with 0-2 R¹⁰), —(CH₂)_(m)-(phenyl substituted with 0-1 R¹⁰), —(CH₂)_(m)-(pyridinyl substituted with 0-1 R¹⁰), and —(CH₂)_(m)-(isoxazolyl substituted with 0-1 R¹⁰);

R^(4a), at each occurrence, is independently selected from: H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, and cyclopropyl;

R⁵, at each occurrence, is independently halogen and C₁₋₆ alkoxy;

R⁶, at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄ alkyl, and C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl; and

R¹⁰ is independently selected from: halogen, CF₃, OCF₃, CN, C₁₋₄ alkyl, and C₁₋₄ alkoxy.

In an eighth aspect, the present disclosure includes a compound of Formula (IV) or (IVa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, within the scope of the seventh aspect.

In a ninth aspect, the present disclosure includes a compound of Formula (IV) or (IVa), or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, within the scope of the seventh or eighth aspect, wherein:

R¹ is independently phenyl substituted with 0-3 R⁶ or pyridinyl substituted with 0-2 R⁶;

R² is independently halogen or C₁₋₄ alkyl;

R³ is independently selected from: CN, cyclohexyl, C₁₋₄ alkoxy substituted with 1 C₁₋₄ alkoxy, phenyl substituted with 0-1 R¹⁰, pyridinyl substituted with 0-1 R¹⁰, and isoxazolyl substituted with 0-1 R¹⁰;

R^(4a) is independently selected from: H, halogen, C₁₋₄ alkyl, and C₁₋₄ alkoxy;

R⁶, at each occurrence, is independently selected from: halogen, C₁₋₄ alkyl, and C₁₋₄ alkoxy; and

R¹⁰, at each occurrence, is independently selected from: halogen, C₁₋₄ alkyl, and C₁₋₄ alkoxy.

In a tenth aspect, the present invention provides a compound selected from the exemplified examples or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides a compound selected from any subset list of compounds or a single compound from the exemplified examples within the scope of any of the above aspects.

In another embodiment, ring A is independently

In another embodiment, ring A is

In another embodiment, ring A is

In another embodiment, the compounds of the present invention have hGPR40 EC₅₀ values ≦5 μM.

In another embodiment, the compounds of the present invention have hGPR40 EC₅₀ values 1 μM.

In another embodiment, the compounds of the present invention have hGPR40 EC₅₀ values 0.5 μM.

In another embodiment, the compounds of the present invention have hGPR40 EC₅₀ values 0.2 μM.

In another embodiment, the compounds of the present invention have hGPR40 EC₅₀ values 0.1 μM.

II. Other Embodiments of the Invention

Additional embodiments of the invention provide for a compound having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.

In another embodiment, the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.

In another embodiment, the present invention provides a process for making a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.

In another embodiment, the present invention provides an intermediate for making a compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s). Examples of additional therapeutic agent(s), according to the present invention include, but are not limited to, anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, and appetite suppressants.

In a preferred embodiment, the present invention provides pharmaceutical composition, wherein the additional therapeutic agents are, for example, a dipeptidyl peptidase-IV (DPP4) inhibitor (for example a member selected from saxagliptin, sitagliptin, vildagliptin, linagliptin, alogliptin, and “BMS DPP4i”), and/or a sodium-glucose transporter-2 (SGLT2) inhibitor (for example a member selected from dapagliflozin, canagliflozin, empagliflozin and remagliflozin).

In a preferred embodiment, the present invention provides pharmaceutical composition, wherein the additional therapeutic agents are, for example, a DPP4 inhibitor (for example a member selected from saxagliptin, sitagliptin, vildagliptin, linagliptin, alogliptin, and “BMS DPP4i”).

In a preferred embodiment, the present invention provides pharmaceutical composition, wherein the additional therapeutic agents are, for example, an SGLT2 inhibitor (for example a member selected from dapagliflozin, canagliflozin, empagliflozin and remagliflozin).

In another embodiment, the present invention provides a method for the treatment of multiple diseases or disorders associated with GPR40, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

Examples of diseases or disorders associated with the activity of the GPR40 that can be prevented, modulated, or treated according to the present invention include, but are not limited to, diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetic kidney disease, acute kidney injury, cardiorenal syndrome, acute coronary syndrome, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, congestive heart failure, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, fatty liver disease, dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), non-cardiac ischemia, pancreatitis, lipid disorders, and liver diseases such as NASH (Non-Alcoholic SteatoHepatitis), NAFLD (Non-Alcoholic Fatty Liver Disease), liver cirrhosis, inflammatory bowel diseases incorporating ulcerative colitis and Crohn's disease, celiac disease, osteoarthritis, nephritis, psoriasis, atopic dermatitis, and skin inflammation.

In another embodiment, the present invention provides a method for the treatment of diabetes, hyperglycemia, gestational diabetes, obesity, dyslipidemia, hypertension and cognitive impairment, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment of diabetes, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment of hyperglycemia, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment of obesity, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment of dyslipidemia, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment of hypertension, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a method for the treatment of cognitive impairment, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention, alone, or, optionally, in combination with another compound of the present invention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a compound of the present invention for use in therapy.

In another embodiment, the present invention provides a compound of the present invention for use in therapy for the treatment of multiple diseases or disorders associated with GPR40.

In another embodiment, the present invention also provides the use of a compound of the present invention for the manufacture of a medicament for the treatment of multiple diseases or disorders associated with GPR40.

In another embodiment, the present invention provides a method for the treatment of multiple diseases or disorders associated with GPR40, comprising administering to a patient in need thereof a therapeutically effective amount of a first and second therapeutic agent, wherein the first therapeutic agent is a compound of the present invention. Preferably, the second therapeutic agent, for example, a DPP4 inhibitor (for example a member selected from saxagliptin, sitagliptin, vildagliptin, linagliptin and alogliptin).

In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in therapy.

In another embodiment, the present invention provides a combined preparation of a compound of the present invention and additional therapeutic agent(s) for simultaneous, separate or sequential use in the treatment of multiple diseases or disorders associated with GPR40.

Where desired, the compound of the present invention may be used in combination with one or more other types of antidiabetic agents and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form or by injection. The other type of antidiabetic agent that may be optionally employed in combination with the GPR40 receptor modulator of the present invention may be one, two, three or more antidiabetic agents or antihyperglycemic agents which may be administered orally in the same dosage form, in a separate oral dosage form, or by injection to produce an additional pharmacological benefit.

The antidiabetic agents used in the combination with the GPR40 receptor modulator of the present invention include, but are not limited to, insulin secretagogues or insulin sensitizers, other GPR40 receptor modulators, or other antidiabetic agents. These agents include, but are not limited to, DPP4 inhibitors (for example, sitagliptin, saxagliptin, alogliptin, linagliptin and vildagliptin), biguanides (for example, metformin and phenformin), sulfonyl ureas (for example, glyburide, glimepiride and glipizide), glucosidase inhibitors (for example, acarbose, miglitol), PPARγ agonists such as thiazolidinediones (for example, rosiglitazone and pioglitazone), PPAR α/γ dual agonists (for example, muraglitazar, tesaglitazar and aleglitazar), glucokinase activators, GPR119 receptor modulators (for example, MBX-2952, PSN821, and APD597), GPR120 receptor modulators (for example, as described in Shimpukade, B. et al., J. Med. Chem., 55(9):4511-4515 (2012)), SGLT2 inhibitors (for example, dapagliflozin, canagliflozin, empagliflozin and remagliflozin), MGAT inhibitors (for example, as described in Barlind, J. G. et al., Bioorg. Med. Chem. Lett., 23(9):2721-2726 (2013)), amylin analogs such as pramlintide, and/or insulin.

The GPR40 receptor modulator of the present invention may also be optionally employed in combination with agents for treating complication of diabetes. These agents include PKC inhibitors and/or AGE inhibitors.

The GPR40 receptor modulator of the present invention may also be optionally employed in combination with one or more hypophagic and/or weight-loss agents such as diethylpropion, phendimetrazine, phentermine, orlistat, sibutramine, lorcaserin, pramlintide, topiramate, MCHR1 receptor antagonists, oxyntomodulin, naltrexone, Amylin peptide, NPY Y5 receptor modulators, NPY Y2 receptor modulators, NPY Y4 receptor modulators, cetilistat, 5HT2c receptor modulators, and the like. The GPR40 receptor modulator of the present invention may also be employed in combination with an agonist of the glucagon-like peptide-1 receptor (GLP-1 R), such as exenatide, liraglutide, GLP-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37), which may be administered via injection, intranasal, or by transdermal or buccal devices.

The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment or embodiments to describe additional embodiments. It is also understood that each individual element of the embodiments is its own independent embodiment. Furthermore, any element of an embodiment is meant to be combined with any and all other elements from any embodiment to describe an additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemical formula or name shall encompass all stereo and optical isomers and racemates thereof where such isomers exist. The term “stereoisomer(s)” refers to compound(s) which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

Many geometric isomers of C═C double bonds, C═N double bonds, ring systems, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.

The present compounds can be isolated in optically active or racemic forms. Optically active forms may be prepared by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention. When enantiomeric or diastereomeric products are prepared, they may be separated by conventional methods, for example, by chromatography or fractional crystallization.

Depending on the process conditions the end products of the present invention are obtained either in free (neutral) or salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may be converted into another form. A free base or acid may be converted into a salt; a salt may be converted into the free compound or another salt; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present invention, free form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are transposed to other parts of the molecules and the chemical bonds between the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.

Unless otherwise indicated, any heteroatom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

As used herein, the term “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C₁ to C₆ alkyl” or “C₁₋₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Alkyl group can be unsubstituted or substituted with at least one hydrogen being replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or “C₀ alkylene” is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either straight or branched configuration having the specified number of carbon atoms and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain. For example, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. For example, “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and butoxy (e.g., n-butoxy, isobutoxy and t-butoxy). Similarly, “alkylthio” or “thioalkoxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example methyl-S— and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl also include “fluoroalkyl” that is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more fluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to include C₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxy include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example trifluoromethyl-S—, and pentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-, bi- or poly-cyclic ring systems. For example, “C₃ to C₆ cycloalkyl” or “C₃₋₆ cycloalkyl” is intended to include C₃, C₄, C₅, and C₆ cycloalkyl groups. Example cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl. Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are included in the definition of “cycloalkyl”. The term “cycloalkenyl” refers to cyclized alkenyl groups. C₄₋₆ cycloalkenyl is intended to include C₄, C₅, and C₆ cycloalkenyl groups. Example cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, and cyclohexenyl.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic residue” is intended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic or tricyclic ring, any of which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, it is intended to include “aryl”. A bridged ring occurs when one or more, preferably one to three, carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclic group” is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group may be attached to its pendant group at any carbon atom which results in a stable structure. The bicyclic carbocyclic group described herein may be substituted on any carbon if the resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or bicyclic aromatic hydrocarbons, including, for example, phenyl, and naphthyl. Aryl moieties are well known and described, for example, in Lewis, R. J., ed., Hawley's Condensed Chemical Dictionary, 13th Edition, John Wiley & Sons, Inc., New York (1997). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.

The term “benzyl”, as used herein, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclic group” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S; and including any polycyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. When the term “heterocycle” is used, it is intended to include heteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, imidazopyridazinyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, pyrimidinyl, pyrazinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl, benzisothiazolyl, imidazolopyridinyl, imidazopyridazinyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl, pyrazolopyridinyl and pyrazolopyrimidinyl.

Examples of 5- to 6-membered heterocycles include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl, pyrimidinyl, imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclic heterocyclic group” is intended to mean a stable 9- or 10-membered heterocyclic ring system which contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, O and S. Of the two fused rings, one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second ring. The second ring is a 5- or 6-membered monocyclic ring which is saturated, partially unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic group described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl” is intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted or unsubstituted. The nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), wherein p is 0, 1 or 2).

Examples of 5- to 6-membered heteroaryls include, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl, triazinyl, and triazolyl.

Bridged rings are also included in the definition of heterocycle. A bridged ring occurs when one or more, preferably one to three, atoms (i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate or a positively charged species such as sodium (Na+), potassium (K+), calcium (Ca²⁺)ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

As used herein, the term “amine protecting group” means any group known in the art of organic synthesis for the protection of amine groups which is stable to an ester reducing agent, a disubstituted hydrazine, R4-M and R7-M, a nucleophile, a hydrazine reducing agent, an activator, a strong base, a hindered amine base and a cyclizing agent. Such amine protecting groups fitting these criteria include those listed in Wuts, P. G. M. et al., Protecting Groups in Organic Synthesis, Fourth Edition, Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Examples of amine protecting groups include, but are not limited to, the following: (1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; (5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilane such as trimethylsilane; (7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such as triphenylmethyl, methyl, and benzyl; and substituted alkyl types such as 2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilane types such as trimethylsilane.

As referred to herein, the term “substituted” means that at least one hydrogen atom is replaced with a non-hydrogen group, provided that normal valencies are maintained and that the substitution results in a stable compound. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the present invention, these may be converted to N-oxides by treatment with an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, shown and claimed nitrogen atoms are considered to cover both the shown nitrogen and its N-oxide (NO) derivative.

When any variable occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R, then said group may optionally be substituted with up to three R groups, and at each occurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate with a reasonable benefit/risk ratio.

Compounds of the present invention can form salts which are also within the scope of this invention. Unless otherwise indicated, reference to an inventive compound is understood to include reference to one or more salts thereof. Pharmaceutically acceptable salts are preferred. However, other salts may be useful, e.g., in isolation or purification steps which may be employed during preparation, and thus, are contemplated within the scope of the invention.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Allen, L. V., Jr., ed., Remington: The Science and Practice of Pharmacy, 22nd Edition, Pharmaceutical Press, London, UK (2012), the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (i.e., a compound of Formula (I)) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art. For examples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985); -   b) Widder, K. et al., eds., Methods in Enzymology, 112:309-396,     Academic Press (1985); -   c) Bundgaard, H., Chapter 5: “Design and Application of Prodrugs”, A     Textbook of Drug Design and Development, pp. 113-191,     Krogsgaard-Larsen, P. et al., eds., Harwood Academic Publishers     (1991); -   d) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992); -   e) Nielsen, N. M. et al., J. Pharm. Sci., 77:285 (1988); -   f) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and -   g) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods and     Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

Compounds containing a carboxy group can form physiologically hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield Formula (I) compounds per se. Such prodrugs are preferably administered orally since hydrolysis in many instances occurs principally under the influence of the digestive enzymes. Parenteral administration may be used where the ester per se is active, or in those instances where hydrolysis occurs in the blood. Examples of physiologically hydrolyzable esters of compounds of formula I include C₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well known physiologically hydrolyzable esters used, for example, in the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques known in the art.

Preparation of prodrugs is well known in the art and described in, for example, King, F. D., ed., Medicinal Chemistry: Principles and Practice, The Royal Society of Chemistry, Cambridge, UK (Second Edition, reproduced (2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich, Switzerland (2003); Wermuth, C. G., ed., The Practice of Medicinal Chemistry, Third Edition, Academic Press, San Diego, Calif. (2008).

The present invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H (also represented as ‘D’ for deuterium) and ³H, carbon such as ¹¹C, ¹³C, and ¹⁴C, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O, and ¹⁸O. Certain isotopically-labeled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, ³H, and carbon-14, ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increase in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁵O, and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

The term “solvate” means a physical association of a compound of this invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be present in a regular arrangement and/or a non-ordered arrangement. The solvate may comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules. “Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.

As used herein, “polymorph(s)” refer to crystalline form(s) having the same chemical structure/composition but different spatial arrangements of the molecules and/or ions forming the crystals. Compounds of the present invention can be provided as amorphous solids or crystalline solids. Lyophilization can be employed to provide the compounds of the present invention as a solid.

Abbreviations as used herein, are defined as follows: “1×” for once, “2×” for twice, “3×” for thrice, “Å” for “Angstroms”, “° C.” for degrees Celsius, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “L” for liter or liters, “mL or ml” for milliliter or milliliters, “μL” for microliter or microliters, “N” for normal, “M” for molar, “N” for normal, “mmol” for millimole or millimoles, “min” for minute or min, “h” for hour or h, “rt” for room temperature, “RT” for retention time, “atm” for atmosphere, “psi” for pounds per square inch, “conc.” for concentrate, “aq” for “aqueous”, “sat” or “sat′d” for saturated, “MW” for molecular weight, “mp” for melting point, “MS” or “Mass Spec” for mass spectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR” for high resolution, “HRMS” for high resolution mass spectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC” for high pressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “RP-Prep. HPLC” for reverse phase preparative HPLC, “TLC” or “tic” for thin layer chromatography, “NMR” for nuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhauser effect spectroscopy, “H” for proton, “δ” for delta, “s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar to one skilled in the art.

-   AcCl acetyl chloride -   Ac₂O acetic anhydride -   AcOH acetic acid -   ADDP 1,1′-(azodicarbonyl)dipiperidine -   Ag₂O silver oxide -   atm atmosphere -   9-BBN 9-borabicyclo[3.3.1]nonane -   BF₃.OEt₂ boron trifluoride diethyl etherate -   BF₃.SMe₂ boron trifluoride dimethyl sulfide -   BH₃.DMS borane dimethyl sulfide complex -   Bn benzyl -   Boc tert-butyloxycarbonyl -   Boc₂O di-tert-butyl dicarbonate -   Bu butyl -   n-BuOH n-butanol -   Bu₃P tributylphosphine -   CDCl₃ deutero-chloroform -   CD₂Cl₂ deutero-dichloromethane -   cDNA complimentary DNA -   CH₂Cl₂ or DCM dichloromethane -   CH₃CN or MeCN acetonitrile -   CHCl₃ chloroform -   CSA camphorsulfonic acid -   Cs₂CO₃ cesium carbonate -   Cu(OAc)₂ copper(II) acetate -   CuI copper(I) iodide -   CuBr.SMe₂ copper(I) bromide dimethylsulfide complex -   DAST (diethylamino)sulfur trifluoride -   DBAD di-tert-butyl azodicarboxylate -   DEAD diethyl azodicarboxylate -   DIAD diisopropyl azodicarboxylate -   DIPEA diisopropylethylamine -   DMAP 4-(dimethylamino)pyridine -   DMF dimethyl formamide -   DMSO dimethyl sulfoxide -   DtBPF 1,1′-bis(di-tert-butylphosphino)ferrocene -   EDTA ethylenediaminetetraacetic acid -   Et ethyl -   Et₂O diethyl ether -   EtOAc ethyl acetate -   EtOH ethanol -   H₂ molecular hydrogen -   H₂O₂ hydrogen peroxide -   H₂SO₄ sulfuric acid -   HCl hydrochloric acid -   Hex hexanes -   i-Bu isobutyl -   i-Pr isopropyl -   i-PrOH or IPA isopropanol -   KCN potassium cyanide -   K₂CO₃ potassium carbonate -   K₂HPO₄ dipotassium phosphate -   KHSO₄ potassium bisulfate -   KI potassium iodide -   KOH potassium hydroxide -   KOtBu potassium tert-butoxide -   K₃PO₄ tripotassium phosphate -   LAH lithium aluminum hydride -   LDA lithium diisopropylamide -   L.G. leaving group -   LHMDS lithium hexamethyldisilazide -   LiBH₄ lithium borohydride -   LiOH lithium hydroxide -   L-Selectride lithium tri-sec-butylborohydride -   Me methyl -   MeI iodomethane -   MeLi methyl lithium -   MeOH methanol -   MgSO₄ magnesium sulfate -   MsCl methanesulfonyl chloride -   NaDCC sodium dichloroisocyanurate -   NaHMDS sodium hexamethyldisilazide -   NaNO₂ sodium nitrite -   Na₂SO₄ sodium sulfate -   Na₂S₂O₃ sodium thiosulfate -   NaBH₄ sodium borohydride -   NaCl sodium chloride -   NaCN sodium cyanide -   NCS N-chlorosuccinimide -   NaH sodium hydride -   NaHCO₃ sodium bicarbonate -   NaOH sodium hydroxide -   NaOtBu sodium tert-butoxide -   NH₃ ammonia -   NH₄Cl ammonium chloride -   NH₄OH ammonium hydroxide -   Pd(OAc)₂ palladium(II) acetate -   Pd/C palladium on carbon -   PdCl₂(dppf)     1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride -   PdCl₂(dtbpf)     [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) -   PdCl₂(PPh₃)₂ bis(triphenylphosphine)palladium(II) dichloride -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0) -   Pd(Ph₃P)₄ tetrakis(triphenylphosphine)palladium(0) -   P.G. protecting group -   Ph phenyl -   Ph₃P triphenylphosphine -   Pr propyl -   PS polystyrene -   PtO₂ platinum(IV) oxide -   SFC supercritical fluid chromatography -   SiO₂ silica oxide -   SPhos 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl -   SPhos precatalyst     chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)     [2-(2-aminoethylphenyl)]palladium(II)-methyl-t-butyl ether adduct -   TBAB tetrabutylammonium bromide -   TBAF tetrabutylammonium fluoride -   t-Bu tert-butyl -   TBDPS-Cl tert-butylchlorodiphenylsilane -   TBS-Cl tert-butyldimethylsilyl chloride -   TBSOTf tert-butyldimethylsilyl trifluoromethanesulfonate -   TCCA trichloroisocyanuric acid -   TEA or NEt₃ triethylamine -   TEMPO 2,2,6,6-tetramethyl-1-piperidinyloxy -   TFA trifluoroacetic acid -   Tf₂O trifluoromethanesulfonic anhydride -   THF tetrahydrofuran -   TMS-Cl chlorotrimethylsilane -   TsCl 4-methylbenzene-1-sulfonyl chloride -   TsNHNH₂ para-toluenesulfonyl hydrazide -   TsOH or pTsOH para-toluenesulfonic acid -   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using the reactions and techniques described in this section. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. Restrictions to the substituents that are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.

Synthesis

The compounds of Formula (I) may be prepared by the exemplary processes described in the following schemes and working examples, as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples. Protection and de-protection in the processes below may be carried out by procedures generally known in the art (see, for example, Wuts, P. G. M. et al., Protecting Groups in Organic Synthesis, Fourth Edition, Wiley (2007)). General methods of organic synthesis and functional group transformations are found in: Trost, B. M. et al., eds., Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, N.Y. (1991); Smith, M. B. et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Sixth Edition, Wiley & Sons, New York, N.Y. (2007); Katritzky, A. R. et al., eds., Comprehensive Organic Functional Groups Transformations II, Second Edition, Elsevier Science Inc., Tarrytown, N.Y. (2004); Larock, R. C., Comprehensive Organic Transformations, VCH Publishers, Inc., New York, N.Y. (1999), and references therein.

Methods for synthesis of a large variety of substituted pyrrolidine compounds useful as starting materials for the preparation of compounds of the present invention are well known in the art. For examples of methods useful for the preparation of pyrrolidine materials see the following references and citations therein: Katritzky et al., eds., Comprehensive Heterocyclic Chemistry, Pergamon Press Inc., New York (1996); Bellina, F. et al., Tetrahedron, 62:7213 (2006); Wolfe, J. P., Eur. J. Org. Chem., 571 (2007); Deng, Q.-H. et al., Organic Letters, 10:1529 (2008); Pisaneschi, F. et al., Synlett, 18:2882 (2007); Najera, C. et al., Angewandte Chemie, International Edition, 44(39):6272 (2005); Sasaki, N. A., Methods in Molecular Medicine, 23(Peptidomimetics Protocols):489 (1999); Zhou, J.-Q. et al., Journal of Organic Chemistry, 57(12):3328 (1992); Coldham, I. et al., Tetrahedron Letters, 38(43):7621 (1997); Schlummer, B. et al., Organic Letters, 4(9):1471 (2002); Larock, R. C. et al., Journal of Organic Chemistry, 59(15):4172 (1994); Galliford, C. V. et al., Organic Letters, 5(19):3487 (2003); Kimura, M. et al., Angewandte Chemie, International Edition, 47(31):5803 (2008); Ney, J. E. et al., Adv. Synth. Catal., 347:1614 (2005); Paderes, M. C. et al., Organic Letters, 11(9):1915 (2009); Wang, Y.-G. et al., Organic Letters, 11(9):2027 (2009); Cordero, F. M. et al., Journal of Organic Chemistry, 74(11):4225 (2009); Hoang, C. T. et al., Journal of Organic Chemistry, 74(11):4177 (2009). Luly, J. R. et al., Journal of the American Chemical Society, 105:2859 (1983); Kimball, F. S. et al., Bioorganic and Medicinal Chemistry, 16:4367 (2008); Bertrand, M. B. et al., Journal of Organic Chemistry, 73(22):8851 (2008); Browning, R. G. et al., Tetrahedron, 60:359 (2004); Ray, J. K. et al., Bioorganic and Medicinal Chemistry, 2(12):1417 (1994); Evans, G. L. et al., Journal of the American Chemical Society, 72:2727 (1950); Stephens, B. E. et al., Journal of Organic Chemistry, 74(1):254 (2009); Spangenberg, T. et al., Organic Letters, 11(2):261 (2008); and Qiu, X.-L. et al., Journal of Organic Chemistry, 67(20):7162 (2008).

Compounds of Formula (I) may be synthesized starting with prolinol A via coupling to Intermediate B using CuI as a catalyst and NaOH as base, for example, to give pyrrolidine C as depicted in Scheme 1. Activation of the hydroxyl C, via MsCl, for example, and displacement with NaCN leads to nitrile D. Nitrile D can be converted to compounds of Formula (I) by hydrolysis, using NaOH, for example.

Compounds of Formula (I) may be synthesized starting with aryl carboxylic acids F via coupling to boronic acids E to give carboxylic acid G as depicted in Scheme 2. Reduction of the carboxylic acid G, via LAH, for example, and mesylation and displacement with LiBr leads to benzyl bromide H. Benzyl bromide H can be converted to the organozinc reagent I and coupled with intermediate J, which could be synthesized employing methods depicted in Scheme 1 to give coupled product D. Intermediate D could be converted to compounds of Formula (I) by hydrolysis, via NaOH, for example.

Alternatively, compounds of Formula (I) may be synthesized beginning with carboxylic acid K, as demonstrated in Scheme 3. The acid can be reduced with a hydride source, such as LAH, and then oxidized to the aldehyde L, possibly using a Swern oxidation. The L.G. in L can be cross-coupled to a boronic acid E using a catalyst, such as Pd(Ph₃P)₄ to give coupled product M. The aldehyde can be transformed to the hydrazide using TsNHNH₂. The hydrazide can be reacted with a boronic acid N using a base, e.g., K₂CO₃, to give coupled product B. Intermediate B could be converted to compounds of Formula (I) following the procedure of Scheme 1.

IV. Biology

Diabetes mellitus is a serious disease afflicting over 100 million people worldwide. It is diagnosed as a group of disorders characterized by abnormal glucose homeostasis resulting in elevated blood glucose. Diabetes is a syndrome with interrelated metabolic, vascular, and neuropathic components. The metabolic abnormality is generally characterized by hyperglycemia and alterations in carbohydrate, fat and protein metabolism caused by absent or reduced insulin secretion and/or ineffective insulin secretion. The vascular syndrome consists of abnormalities in the blood vessels leading to cardiovascular, retinal and renal complications. Abnormalities in the peripheral and autonomic nervous systems are also part of diabetic syndrome. Strikingly, diabetes is the fourth leading cause of global death by disease, the largest cause of kidney failure in developed countries, the leading cause of vision loss in industrialized countries and has the greatest prevalence increase in developing countries.

Type 2 diabetes, which accounts for 90% of diabetes cases, is characterized by increasing insulin resistance associated with inadequate insulin secretion after a period of compensatory hyperinsulinemia. The reasons for 0 cell secondary failure are not completely understood. Acquired pancreatic islet damage or exhaustion and/or genetic factors causing susceptibility to islet secretory insufficiency have been hypothesized.

Free fatty acids (FFAs) are evidenced to influence insulin secretion from β cells primarily by enhancing glucose-stimulated insulin secretion (GSIS). Although glucose is recognized as the major stimulator of insulin secretion from β cells, other stimuli, such as amino acids, hormones, and FFAs, also regulate insulin secretion. Thus, under normal settings, insulin secretion from β cells in response to food intake is evoked by the collective stimuli of nutrients, such as glucose, amino acids, and FFAs, and hormones like the incretin glucagon-like peptide 1 (GLP-1). Fatty acids are also known to stimulate the secretion of several gut satiety hormones, including cholocystokinine (CCK), GLP-1, and peptide YY (PYY).

G-protein coupled receptors (GPCRs) expressed in cells are known to modulate the release of insulin in response to changes in plasma glucose levels. GPR40, also known as fatty acid receptor 1 (FFAR1), is a membrane-bound FFA receptor which is preferentially expressed in the pancreatic islets and specifically in β cells. GPR40 (e.g., human GPR40, RefSeq mRNA ID NM_005303; e.g., mouse GPR40 RefSeq mRNA ID NM_194057) is a GPCR located at chromosome 19q13.12. GPR40 is activated by medium to long chain fatty acids and thereby triggering a signaling cascade that results in increased levels of [Ca²⁺]_(i) in β cells and subsequent stimulation of insulin secretion (Itoh et al., Nature, 422:173-176 (2003)). Selective small molecule agonists of GPR40 have been shown to promote GSIS and reduce blood glucose in mice (Tan et al., Diabetes, 57:2211-2219 (2008)). Briefly, when activators of GPR40 are administered to either normal mice or mice that are prone to diabetes due to genetic mutation, prior to a glucose tolerance test, improvements in glucose tolerance are observed. A short-lived increase in plasma insulin levels are also observed in these treated mice. It has also been shown that GPR40 agonists restore GSIS in pancreatic β-cells from the neonatal STZ rats suggesting that GPR40 agonists will be efficacious in diabetics with compromised β-cell function and mass. Fatty acids are known to stimulate the secretion of several gut satiety hormones, including cholocystokinine (CCK), GLP-1, and peptide YY (PYY), and GPR40 has been shown to colocalize with cells that secrete such hormones (Edfalk et al., Diabetes, 57:2280-2287 (2008) Luo et al., PLoS ONE, 7:1-12 (2012)). Fatty acids are also known to play a role in neuronal development and function, and GPR40 has been reported as a potential modulator of the fatty acid effects on neurons (Yamashima, T., Progress in Neurobiology, 84:105-115 (2008)).

Given the increase in the worldwide patient population afflicted by type 2 diabetes, there is a need for novel therapies which are effective with minimal adverse events. To decrease medical burden of type 2 diabetes through enhanced glycemic control, GPR40 modulator compounds of the present invention are being investigated here for their incretin effect to promote GSIS as well as the potential combination with a broad range of anti-diabetic drugs.

The term “modulator” refers to a chemical compound with capacity to either enhance (e.g., “agonist” activity) or partially enhance (e.g., “partial agonist” activity) or inhibit (e.g., “antagonist” activity or “inverse agonist” activity) a functional property of biological activity or process (e.g., enzyme activity or receptor binding); such enhancement or inhibition may be contingent on the occurrence of a specific event, such as activation of a signal transduction pathway, receptor internalization, and/or may be manifest only in particular cell types.

It is also desirable and preferable to find compounds with advantageous and improved characteristics compared with known anti-diabetic agents, in one or more of the following categories that are given as examples, and are not intended to be limiting: (a) pharmacokinetic properties, including oral bioavailability, half life, and clearance; (b) pharmaceutical properties; (c) dosage requirements; (d) factors that decrease blood drug concentration peak-to-trough characteristics; (e) factors that increase the concentration of active drug at the receptor; (f) factors that decrease the liability for clinical drug-drug interactions; (g) factors that decrease the potential for adverse side-effects, including selectivity versus other biological targets; and (h) improved therapeutic index with less propensity for hypoglycemia.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-human organism that could potentially benefit from treatment with a GPR40 modulator. Exemplary subjects include human beings of any age with risk factors for metabolic disease. Common risk factors include, but are not limited to, age, sex, weight, family history, or signs of insulin resistance such as acanthosis nigricans, hypertension, dislipidemia, or polycystic ovary syndrome (PCOS).

As used herein, “treating” or “treatment” cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e., arresting it development; (b) relieving the disease-state, i.e., causing regression of the disease state; and/or (c) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it.

As used herein, “preventing” or “prevention” cover the preventive treatment (i.e., prophylaxis and/or risk reduction) of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the probability of the occurrence of a clinical disease-state. Patients are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. “Prophylaxis” therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.

As used herein, “risk reduction” covers therapies that lower the incidence of development of a clinical disease state. As such, primary and secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of a compound of the present invention that is effective when administered alone or in combination to modulate GPR40 and/or to prevent or treat the disorders listed herein. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the preventive or therapeutic effect, whether administered in combination, serially, or simultaneously.

In Vitro GPR40 Assays FDSS-Based Intracellular Calcium Assay

Cell lines expressing GPR40 are generated using the pDEST-3xFLAG gene expression system and are cultured in culture medium comprising the following components: F12 (Gibco #11765), 10% lipid deprived fetal bovine serum, 250 μg/ml zeocin and 500 μg/ml G418. To conduct the fluorescent imaging plate reader (FLIPR)-based calcium flux assay to measure intracellular Ca²⁺ response, cells expressing GPR40 are plated on 384 well plates (BD Biocoat #356697) at a density of 20,000 cells/20 μL medium per well in phenol red and serum-free DMEM (Gibco #21063-029) and incubated overnight. Using BD kit #s 80500-310 or -301, the cells are incubated with 20 μL per well of Hank's buffered salt solution with 1.7 mM probenecid and Fluo-3 at 37° C. for 30 min. Compounds are dissolved in DMSO and diluted to desired concentrations with assay buffer and added to the cells as 3× solution (20 μL per well). Run fluorescence/luminescence reader FDSS (Hamamatsu) to read intracellular Ca²⁺ response.

The exemplified Examples disclosed below were tested in the Human GRP40 In Vitro assay described above and found having hGRP40 modulating activity.

GPR40 IP-One HTRF Assays in HEK293/GPR40 Inducible Cell Lines

Human, mouse and rat GPR40-mediated intracellular IP-One HTRF assays were established using human embryonic kidney HEK293 cells stably transfected with a tetracycline-inducible human, mouse or rat GPR40 receptor. Cells were routinely cultured in growth medium containing DMEM (Gibco Cat. #12430-047), 10% qualified FBS (Sigma, Cat. #F2442), 200 μg/mL hygromycin (Invitrogen, Cat. #16087-010) and 1.5 μg/mL blasticidin (Invitrogen, Cat. #R210-01). About 12-15 million cells were passed into a T175 tissue culture flask (BD Falcon 353112) with growth medium and incubated for 16-18 hours (overnight) at 37° C. with 5% CO₂. The next day, assay medium was exchanged with growth medium containing 1000 ng/mL of tetracycline (Fluka Analytical, Cat. #87128) to induce GPR40 expression for 18-24 hours at 37° C. incubator with 5% CO₂. After induction, the cells were washed with PBS (Gibco, Cat. #14190-036) and detached with Cell Stripper (Cellgro, Cat. #25-056-CL). 10-20 mL growth medium were added to the flask and cells were collected in 50 mL tubes (Falcon, Cat. #352098) and spun at 1000 RPM for 5 minutes. Culture medium was aspirated and the cells were resuspended in 10 mL of 1× IP-One Stimulation Buffer from the Cisbio IP-One kit (Cisbio, Cat. #62IPAPEJ). The cells were diluted to 1.4×106 cells/mL in Stimulation Buffer.

Test compounds were 3-fold, 11-point serially diluted in DMSO in a REMP assay plate (Matrix Cat. #4307) by Biocel (Agilent). The compounds were transferred into an Echo plate (Labcyte, Cat. #LP-0200) and 20 nL of diluted compounds were transferred to an assay plate (proxi-plate from Perkin Elmer, Cat. #6008289) by Echo acoustic nano dispenser (Labcyte, model ECHO550). 14 μL of the diluted cells were then added to the assay plate by Thermo (SN 836 330) CombiDrop and incubated at room temperature for 45 minutes. Then 3 μL of IP1 coupled to dye D2 from the Cisbio IP-One kit were added to the assay plate followed by 3 μL of Lumi4-Tb cryptate K from the kit. The plate was further incubated at room for 1 hour before reading on the Envision (Perkin Elmer Model 2101) with an HTRF protocol. Activation data for the test compound over a range of concentrations was plotted as percentage activation of the test compound (100%=maximum response). After correcting for background [(sample read−mean of low control)/(mean of high control−mean of low control)](low control is DMSO without any compound), EC₅₀ values were determined. The EC₅₀ is defined as the concentration of test compound which produces 50% of the maximal response and was quantified using the 4 parameter logistic equation to fit the data. The maximal Y value observed (% Ymax) was calculated relative to a BMS standard reference compound at a final concentration of 0.625 μM.

Some of the exemplified Examples disclosed below were tested in the Human GRP40 In Vitro assay described above and found having hGRP40 modulating activity reported as hGPR40 IP1 EC₅₀.

BMS DPP4i—Reference Compound

BMS DPP4i is disclosed in Simpkins, L. et al., Bioorganic Medicinal Chemistry Letters, 17(23):6476-6480 (2007) (compound 48) and in WO 2005/012249 (Example 3). BMS DPP4i has the following formula:

The compounds of the present invention possess activity as modulators of GPR40, and, therefore, may be used in the treatment of diseases associated with GPR40 activity. Via modulation of GPR40, the compounds of the present invention may preferably be employed to modulate the production/secretion of insulin and/or gut hormones, such as GLP-1, GIP, CCK and amylin.

Accordingly, the compounds of the present invention can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to, treating, preventing, or slowing the progression of diabetes and related conditions, microvascular complications associated with diabetes, macrovascular complications associated with diabetes, cardiovascular diseases, Metabolic Syndrome and its component conditions, inflammatory diseases and other maladies. Consequently, it is believed that the compounds of the present invention may be used in preventing, inhibiting, or treating diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetic kidney disease, acute kidney injury, cardiorenal syndrome, acute coronary syndrome, delayed wound healing, atherosclerosis and its sequelae (acute coronary syndrome, myocardial infarction, angina pectoris, peripheral vascular disease, intermittent claudication, myocardial ischemia, stroke, heart failure), Metabolic Syndrome, hypertension, obesity, fatty liver disease, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, high LDL, vascular restenosis, peripheral arterial disease, lipid disorders, liver diseases such as NASH (Non-Alcoholic SteatoHepatitis), NAFLD (Non-Alcoholic Fatty Liver Disease) and liver cirrhosis, neurodegenerative disease, cognitive impairment, dementia, and treatment of side-effects related to diabetes, lipodystrophy and osteoporosis from corticosteroid treatment.

Metabolic Syndrome or “Syndrome X” is described in Ford et al., J. Am. Med. Assoc., 287:356-359 (2002) and Arbeeny et al., Curr. Med. Chem.—Imm., Endoc. & Metab. Agents, 1:1-24 (2001).

GPR40 is expressed in neuronal cells, and is associated with development and maintenance of neuronal health in brain, as described in Yamashima, T., Progress in Neurobiology, 84:105-115 (2008).

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered for any of the uses described herein by any suitable means, for example, orally, such as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as in the form of suppositories. They can be administered alone, but generally will be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising a compound of the invention in combination with at least one additional pharmaceutically acceptable carrier. A “pharmaceutically acceptable carrier” refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular, mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents and dispensing agents, depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to a number of factors well within the purview of those of ordinary skill in the art. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, binders, etc., well known to those of ordinary skill in the art. Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources such as, for example, Allen, L. V., Jr. et al., Remington: The Science and Practice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press (2012).

The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired.

By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to about 5000 mg per day, preferably between about 0.01 to about 1000 mg per day, and most preferably between about 0.1 to about 250 mg per day. Intravenously, the most preferred doses will range from about 0.01 to about 10 mg/kg/minute during a constant rate infusion. Compounds of this invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The compounds are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutical carriers) suitably selected with respect to the intended form of administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with conventional pharmaceutical practices.

Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 2000 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of the compounds of the present invention (250 mg), lactose (75 mg), and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing at least one of the compounds of the present invention (250 mg) into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of physiological saline, to produce an injectable preparation.

The present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of the present invention, alone or in combination with a pharmaceutical carrier. Optionally, compounds of the present invention can be used alone, in combination with other compounds of the invention, or in combination with one or more other therapeutic agent(s), e.g., an antidiabetic agent or other pharmaceutically active material.

The compounds of the present invention may be employed in combination with other GPR40 modulators or one or more other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, and appetite suppressants.

Where desired, the compound of the present invention may be used in combination with one or more other types of antidiabetic agents and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form or by injection. The other type of antidiabetic agent that may be optionally employed in combination with the GPR40 receptor modulator of the present invention may be one, two, three or more antidiabetic agents or antihyperglycemic agents which may be administered orally in the same dosage form, in a separate oral dosage form, or by injection to produce an additional pharmacological benefit.

The antidiabetic agents used in the combination with the compound of the present invention include, but are not limited to, insulin secretagogues or insulin sensitizers, other GPR40 receptor modulators, or other antidiabetic agents. These agents include, but are not limited to, dipeptidyl peptidase IV inhibitors (DPP4i; for example, sitagliptin, saxagliptin, alogliptin, vildagliptin), biguanides (for example, metformin, phenformin), sulfonyl ureas (for example, gliburide, glimepiride, glipizide), glucosidase inhibitors (for example, acarbose, miglitol), PPARγ agonists such as thiazolidinediones (for example, rosiglitazone, pioglitazone), PPAR α/γ dual agonists (for example, muraglitazar, tesaglitazar, aleglitazar), glucokinase activators (as described in Fyfe, M. C. T. et al., Drugs of the Future, 34(8):641-653 (2009) and incorporated herein by reference), other GPR40 receptor modulators (e.g., TAK-875), GPR119 receptor modulators (for example, MBX-2952, PSN821, APD597), GPR120 receptor modulators (for example, as described in Shimpukade, B. et al., J. Med. Chem., 55(9):4511-4515 (2012)), sodium-glucose transporter-2 (SGLT2) inhibitors (for example dapagliflozin, canagliflozin, empagliflozin, remagliflozin), 11b-HSD-1 inhibitors (for example MK-0736, B135585, BMS-823778, and LY2523199), MGAT inhibitors (for example, as described in Barlind, J. G. et al., Bioorg. Med. Chem. Lett. (2013), doi: 10.1016/j.bmcl.2013.02.084), amylin analogs such as pramlintide, and/or insulin. Reviews of current and emerging therapies for the treatment of diabetes can be found in: Mohler, M. L. et al., Medicinal Research Reviews, 29(1):125-195 (2009), and Mizuno, C. S. et al., Current Medicinal Chemistry, 15:61-74 (2008).

The GPR40 receptor modulator of formula I may also be optionally employed in combination with agents for treating complication of diabetes. These agents include PKC inhibitors and/or AGE inhibitors.

The GPR40 receptor modulator of formula I way also be optionally employed in combination with one or more hypophagic agents such as diethylpropion, phendimetrazine, phentermine, orlistat, sibutramine, lorcaserin, pramlintide, topiramate, MCHR1 receptor antagonists, oxyntomodulin, naltrexone, Amylin peptide, NPY Y5 receptor modulators, NPY Y2 receptor modulators, NPY Y4 receptor modulators, cetilistat, 5HT2c receptor modulators, and the like. The compound of structure I may also be employed in combination with an agonist of the glucagon-like peptide-1 receptor (GLP-1 R), such as exenatide, liraglutide, GPR-1(1-36) amide, GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492 to Habener, the disclosure of which is incorporated herein by reference), which may be administered via injection, intranasal, or by transdermal or buccal devices. Reviews of current and emerging therapies for the treatment of obesity can be found in: Melnikova, I. et al., Nature Reviews Drug Discovery, 5:369-370 (2006); Jones, D., Nature Reviews: Drug Discovery, 8:833-834 (2009); Obici, S., Endocrinology, 150(6):2512-2517 (2009); and Elangbam, C. S., Vet. Pathol., 46(1):10-24 (2009).

The above other therapeutic agents, when employed in combination with the compounds of the present invention may be used, for example, in those amounts indicated in the Physicians' Desk Reference, as in the patents set out above, or as otherwise determined by one of ordinary skill in the art.

Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of the present invention and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced). For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a material that affects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. By “administered in combination” or “combination therapy” it is meant that the compound of the present invention and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination, each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.

The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the GPR40 receptor. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving GPR40 or anti-diabetic activity. For example, a compound of the present invention could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure the experimentor that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds according to the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnostic assays involving GPR40.

The present invention also encompasses an article of manufacture. As used herein, article of manufacture is intended to include, but not be limited to, kits and packages. The article of manufacture of the present invention, comprises: (a) a first container; (b) a pharmaceutical composition located within the first container, wherein the composition, comprises: a first therapeutic agent, comprising a compound of the present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package insert stating that the pharmaceutical composition can be used for the treatment of multiple diseases or disorders associated with GPR40 (as defined previously). In another embodiment, the package insert states that the pharmaceutical composition can be used in combination (as defined previously) with a second therapeutic agent for the treatment of multiple diseases or disorders associated with GPR40. The article of manufacture can further comprise: (d) a second container, wherein components (a) and (b) are located within the second container and component (c) is located within or outside of the second container. Located within the first and second containers means that the respective container holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceutical composition. This container can be for manufacturing, storing, shipping, and/or individual/bulk selling. First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation), or any other container used to manufacture, hold, store, or distribute a pharmaceutical product.

The second container is one used to hold the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks. The package insert can be physically attached to the outside of the first container via tape, glue, staple, or another method of attachment, or it can rest inside the second container without any physical means of attachment to the first container. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, it is preferable that the package insert is physically attached via tape, glue, staple, or another method of attachment. Alternatively, it can be adjacent to or touching the outside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recites information relating to the pharmaceutical composition located within the first container. The information recited will usually be determined by the regulatory agency governing the area in which the article of manufacture is to be sold (e.g., the United States Food and Drug Administration). Preferably, the package insert specifically recites the indications for which the pharmaceutical composition has been approved. The package insert may be made of any material on which a person can read information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information has been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.

EXAMPLES

The following Examples are offered as illustrative, as a partial scope and particular embodiments of the invention and are not meant to be limiting of the scope of the invention. Abbreviations and chemical symbols have their usual and customary meanings unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the schemes and other methods disclosed herein or may be prepared using the same.

HPLC/MS and Preparatory/Analytical HPLC Methods Employed in Characterization or Purification of Examples

Analytical HPLC/MS (unless otherwise noted) was performed on Shimadzu SCL-10A liquid chromatographs and Waters MICROMASS® ZQ Mass Spectrometers (Desolvation Gas: Nitrogen; Desolvation Temp. 250° C.; Ion Source Temp: 120° C.; Positive Electrospray conditions) using the following method:

Linear Gradient of 0% to 100% Solvent B over 2 min, with 1 minute hold at 100% B;

UV visualization at 220 nm;

Column: PHENOMENEX® Luna C18 (2) 30 mm×4.60 mm; 5 m particle (Heated to Temp. 40° C.);

Flow rate: 5 ml/min;

Solvent A: 10% MeCN-90% H₂O-0.1% TFA; or, 10% MeOH-90% H₂O-0.1% TFA; and

Solvent B: 90% MeCN-10% H₂O-0.1% TFA; or, 90% MeOH-10% H₂O-0.1% TFA.

Preparatory HPLC (unless otherwise noted) was performed on a Shimadzu SCL-10A liquid chromatograph with a linear gradient of 20-100% Solvent B over 10 or 30 min, with either a 2 or 5 min (respectively) hold at 100% Solvent B;

UV visualization at 220 nm;

Column: PHENOMENEX® Luna Axia 5μ C18 30×100 mm;

Flow rate: 20 mL/min;

Solvent A: 10% MeCN-90% H₂O-0.1% TFA; and

Solvent B: 90% MeCN-10% H₂O-0.1% TFA.

Analytical HPLC (unless otherwise noted) was performed to determine compound purity on a Shimadzu SIL-10A using the following method (Unless otherwise stated, retention times listed in Examples refer the retention times of Column 1):

Linear Gradient of 10% to 100% Solvent B over 15 min;

UV visualization at 220 nm and 254 nm;

Column 1: SunFire C18 3.5 μm, 4.6×150 mm;

Column 2: XBridge Phenyl 3.5 μm, 4.6×150 mm;

Flow rate: 1 ml/min (for both columns);

Solvent A: 5% MeCN-95% H₂O-0.05% TFA; and

Solvent B: 95% MeCN-5% H₂O-0.05% TFA.

or

Linear Gradient of stated starting percentage to 100% Solvent B over 8 min;

UV visualization at 220 nm;

Column: ZORBAX® SB C18 3.5 μm, 4.6×75 mm;

Flow rate: 2.5 ml/min;

Solvent A: 10% MeOH-90% H₂O-0.2% H₃PO₄; and

Solvent B: 90% MeOH-10% H₂O-0.2% H₃PO₄.

NMR Employed in Characterization of Examples

¹H NMR spectra (unless otherwise noted) were obtained with JEOL® or Bruker FOURIER® transform spectrometers operating at 400 MHz or 500 MHz. ¹H-nOe experiments were performed in some cases for regiochemistry elucidation with a 400 MHz Bruker FOURIER® Transform spectrometer.

Spectral data are reported as chemical shift (multiplicity, number of hydrogens, coupling constants in Hz) and are reported in ppm (δ units) relative to either an internal standard (tetramethylsilane=0 ppm) for ¹H NMR spectra, or are referenced to the residual solvent peak (2.49 ppm for CD₃SOCD₂H, 3.30 ppm for CD₂HOD, 1.94 for CHD₂CN, 7.26 ppm for CHCl₃, 5.32 ppm for CDHCl₂).

Example 1 2-((2R,4S)-1-(4-((2′-Fluoro-5′-methoxy-3-methylbiphenyl-4-yl)methyl)phenyl)-4-phenylpyrrolidin-2-yl)acetic acid, HCl

1A. (2R,4S)-1-(tert-Butoxycarbonyl)-4-phenylpyrrolidine-2-carboxylic acid: (2R,4S)-4-phenylpyrrolidine-2-carboxylic acid, HCl (0.204 g, 0.897 mmol) was dissolved in a mixture of dioxane (1.7 mL) and water (0.56 mL) and the solution was cooled to 0° C. 1 M aq. NaOH (1.8 mL, 1.8 mmol) and then BOC₂O (0.23 mL, 0.99 mmol) were added and the reaction mixture was warmed to rt and stirred overnight. The reaction mixture was partitioned between water (10 mL) and EtOAc (20 mL). The organic layer was removed. The aqueous layer was mixed with EtOAc (10 mL) and the pH of the biphasic mixture was adjusted with 10% aq. KHSO₄ added dropwise with stirring until pH 2-3. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried (MgSO₄) and concentrated to give 1A (0.278 g, 0.954 mmol, 100% yield) as a colorless oil, which solidified upon standing. LC-MS Anal. Calc'd C₁₆H₂₁NO₄: 291.34. found [M+H] 292.0. ¹H NMR (500 MHz, CDCl₃) δ 7.38-7.30 (m, 2H), 7.28-7.20 (m, 3H), 4.52-4.32 (m, 1H), 4.09-3.97 (m, 1H), 3.35 (br. s., 2H), 2.80-2.59 (m, 1H), 2.47-2.12 (m, 1H), 1.52-1.39 (m, 9H).

1B. (2R,4S)-tert-Butyl 2-(hydroxymethyl)-4-phenylpyrrolidine-1-carboxylate: 1A was dissolved in anhydrous THF (37 mL) and the mixture was cooled to −10° C. 4-Methylmorpholine (0.10 mL, 0.94 mmol) and isobutyl chloroformate (0.12 mL, 0.94 mmol) were then added and the mixture was stirred at −10° C. for 45 min. The mixture was filtered and added dropwise to a solution of NaBH₄ (0.068 g, 1.8 mmol) in water (0.48 mL) cooled to 0° C. The mixture was stirred for 2 h and slowly warmed to rt. The reaction was quenched with sat. aq. NH₄Cl and the product was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to provide 1B (0.207 g, 0.746 mmol, 83% yield) as a colorless oil. LC-MS Anal. Calc'd C₁₆H₂₃NO₃: 277.36. found [M+H] 278.0. ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.28 (m, 2H), 7.25-7.20 (m, 3H), 5.22 (d, J=8.8 Hz, 1H), 4.17-4.04 (m, 1H), 3.98 (br. s., 1H), 3.82-3.72 (m, 1H), 3.71-3.61 (m, 1H), 3.36-3.17 (m, 2H), 2.48-2.34 (m, 1H), 1.74-1.60 (m, 1H), 1.48 (s, 9H).

1C. ((2R,4S)-4-Phenylpyrrolidin-2-yl)methanol hydrochloride: 1B (0.757 g, 2.73 mmol) was dissolved in a 4 N solution of HCl (5.8 mL, 23 mmol) in dioxane and stirred for 1 h. The reaction was concentrated to afford 1C (0.500 g, 2.34 mmol, 86% yield) as a white solid. LC-MS Anal. Calc'd C₁₁H₁₅NO:177.24. found [M+H] 178.0.

1D. (4-Bromo-2-methylphenyl)methanol: To a solution of 4-bromo-2-methylbenzoic acid (10.0 g, 46.5 mmol) in THF (150 mL) at 0° C. was slowly added a 1.0 M solution of BH₃.THF in THF (69.8 mL, 69.8 mmol). The resulting solution was warmed to rt and stirred for 3 h. The reaction mixture was cooled in an ice-water bath and quenched with water slowly. The aqueous layer was extracted with EtOAc (2×100 mL) and the combined extracts was washed with aq. 1 N NaOH, water, and brine, dried over MgSO₄, filtered, and concentrated to give 1D (light yellow solid, 9.30 g, 46.3 mmol, 99% yield), which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.29-7.36 (2H, m), 7.20-7.25 (1H, m), 4.66 (2H, d, J=5.77 Hz), 2.32 (3H, s).

1E. 4-Bromo-2-methylbenzaldehyde: To a solution of 1D (9.30 g, 46.3 mmol) in CH₂Cl₂ (200 mL) under argon was added oxalyl chloride (10.1 mL, 116 mmol) at −78° C.; then DMSO (9.85 mL, 139 mmol) was added dropwise with a venting needle. After the addition was complete, the venting needle was removed and the reaction mixture was stirred at −78° C. under argon for 30 min. Then, NEt₃ (38.7 mL, 278 mmol) was added dropwise. After stirring at the same temperature for 3 h, the reaction mixture was diluted with water (20 mL) and CH₂Cl₂ (50 mL) and the layers were separated. The aqueous layer was further extracted with CH₂Cl₂ (3×100 mL) and the combined organic extracts were washed with water and brine, dried over MgSO₄, filtered, and concentrated. The crude product was purified by silica chromatography to give 1E (yellow oil, 6.70 g, 33.7 mmol, 73% yield). ¹H NMR (400 MHz, CDCl₃) δ 10.22 (1H, s), 7.66 (1H, d, J=8.28 Hz), 7.51 (1H, dd, J=8.28, 1.76 Hz), 7.45 (1H, s), 2.65 (3H, s).

1F. 2-Fluoro-4′-(4-iodobenzyl)-5-methoxy-3′-methylbiphenyl: 1E (6.70 g, 33.7 mmol) and 2-fluoro-5-methoxyphenylboronic acid (6.29 g, 37.0 mmol) were combined in THF (100 mL) and a 2 M aq. solution of K₂CO₃ (50 mL, 100 mmol) was added. The reaction mixture was purged with argon for 5 min and then Pd(Ph₃P)₄ (1.556 g, 1.346 mmol) was added. The reaction mixture was refluxed at 85° C. for 4 h. The reaction mixture was cooled to rt, the layers were separated, and the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water and brine, dried (MgSO₄), filtered, and concentrated. The crude product was purified by silica chromatography to provide 2′-fluoro-5′-methoxy-3-methylbiphenyl-4-carbaldehyde (8.00 g, 29.5 mmol, 88% yield) as a yellow oil. To a solution of 2′-fluoro-5′-methoxy-3-methylbiphenyl-4-carbaldehyde (2.00 g, 8.19 mmol) in 1,4-dioxane (40 mL) was added 4-methylbenzenesulfonohydrazide (1.53 g, 8.19 mmol) and the resulting solution was heated at 80° C. for 90 min with a reflux condenser. Then, 4-iodophenylboronic acid (3.04 g, 12.3 mmol) and K₂CO₃ (1.70 g, 12.3 mmol) were added. The reaction mixture was refluxed at 110° C. for 2 h. The reaction mixture was diluted with EtOAc and water. The aqueous layer was further extracted with EtOAc (2×50 mL) and the combined extracts was washed with water and brine, dried over MgSO₄, filtered, and concentrated. The crude product was purified via silica chromatography to afford 1F (1.90 g, 4.40 mmol, 54% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.65 (2H, m), 7.31-7.39 (2H, m), 7.15 (1H, d, J=7.5 Hz), 7.02-7.10 (1H, m), 6.90-6.97 (3H, m), 6.82 (1H, dt, J=9.0, 3.4 Hz), 3.97 (2H, s), 3.83 (3H, s), 2.29 (3H, s).

1G. ((2R,4S)-1-(4-((2′-Fluoro-5′-methoxy-3-methylbiphenyl-4-yl)methyl) phenyl)-4-phenylpyrrolidin-2-yl)methanol: To a vial of 1F (134 mg, 0.309 mmol), 1C (60 mg, 0.28 mmol), and NaOH (33.7 mg, 0.842 mmol) in n-BuOH (0.56 mL) purged with argon was added CuI (1.3 mg, 7.0 μmol). The reaction was sealed and heated to 90° C. overnight. The reaction mixture was cooled to rt and quenched with sat. aq. NH₄Cl (4 mL). The reaction mixture was extracted with CH₂Cl₂ (3×3 mL). The combined organic layers were washed with sat. aq. NH₄Cl (2×3 mL), brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica chromatography to provide 1G (131 mg, 0.271 mmol, 97% yield) as a colorless oil. LC-MS Anal. Calc'd C₃₂H₃₂FNO₂: 481.60. found [M+H] 482.2. ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.31 (m, 6H), 7.28-7.24 (m, 1H), 7.19 (d, J=7.7 Hz, 1H), 7.10-7.03 (m, 3H), 6.96 (dd, J=3.2, 6.2 Hz, 1H), 6.82 (td, J=3.5, 8.9 Hz, 1H), 6.71-6.65 (m, 2H), 4.10-4.03 (m, 1H), 3.95 (s, 2H), 3.94-3.91 (m, 1H), 3.83 (s, 3H), 3.82-3.76 (m, 1H), 3.71-3.67 (m, 1H), 3.67-3.64 (m, 1H), 3.58 (t, J=9.6 Hz, 1H), 3.41-3.31 (m, 1H), 2.59-2.49 (m, 1H), 2.38 (dd, J=8.8, 11.8 Hz, 1H), 2.35 (s, 3H).

1H. 2-((2R,4S)-1-(4-((2′-Fluoro-5′-methoxy-3-methylbiphenyl-4-yl)methyl) phenyl)-4-phenylpyrrolidin-2-yl)acetonitrile: To a solution of 1G (130 mg, 0.270 mmol) in CH₂Cl₂ (1.4 mL) at 0° C. was added NEt₃ (75 μl, 0.54 mmol) followed by slow addition of MsCl (32 μl, 0.41 mmol). The mixture was stirred and gradually warmed to rt. The reaction was quenched with sat. aq. NaHCO₃. The reaction mixture was extracted with EtOAc (3×3 mL). The combined organic layers were washed with 1 N aq. HCl, sat. aq. NaHCO₃, and brine. The organic layer was dried (MgSO₄) and concentrated. The crude product was dissolved in DMSO (1.4 mL) and NaCN (52.9 mg, 1.08 mmol) was added. The reaction was stirred at 50° C. overnight. The reaction was cooled to rt and quenched with water (3 mL). The product was extracted with CH₂Cl₂ (3×2 mL). The combined organic layers were washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to afford 1H (109 mg, 0.222 mmol, 83% yield) as a colorless oil. LC-MS Anal. Calc'd C₃₃H₃₁FN₂O: 490.61. found [M+H] 491.2.

Example 1

1H (109 mg, 0.222 mmol) was dissolved in EtOH (2.2 mL) and 6 M aq. KOH (741 μl, 4.44 mmol) was added. The reaction tube was sealed and heated to 120° C. for 120 min. The reaction mixture was concentrated and redissolved in EtOAc. The solution was acidified to pH 2 with 1 N aq. HCl and the product was extracted with EtOAc (3×). The combined organic layers were dried (MgSO₄) and concentrated. The crude product was purified by RP-Prep. HPLC. The residue was dissolved in CH₃CN and several mL of 3 N aq. HCl were added. The reaction mixture was concentrated and the procedure was repeated 2×. The aqueous layer was lyophilized overnight to give Example 1 (25 mg, 0.046 mmol, 21% yield) as a white solid. LC-MS Anal. Calc'd C₃₃H₃₂FNO₃: 509.61. found [M+H] 510.0. ¹H NMR (500 MHz, CDCl₃) δ 7.62 (br. s., 2H), 7.48 (d, J=5.8 Hz, 2H), 7.36 (br. s., 4H), 7.28 (d, J=6.1 Hz, 3H), 7.14 (d, J=7.2 Hz, 1H), 7.06 (t, J=9.4 Hz, 1H), 6.94 (br. s., 1H), 6.82 (br. s., 1H), 4.39-4.12 (m, 2H), 4.04 (br. s., 2H), 3.90-3.62 (m, 5H), 3.35 (br. s., 1H), 2.98 (d, J=17.1 Hz, 1H), 2.84 (br. s., 1H), 2.50 (br. s., 1H), 2.28 (br. s., 3H). Analytical HPLC: RT=12.8 min, HI: 99.0%. hGPR40 EC₅₀=15 nM.

Example 2 2-(4-Cyano-1-(4-((2′-fluoro-5′-methoxy-3-methylbiphenyl-4-yl)methyl)phenyl) pyrrolidin-2-yl)acetic acid, TFA

2A. 2-((2R,4R)-4-(Benzyloxy)-1-(4-((2′-fluoro-5′-methoxy-3-methylbiphenyl-4-yl)methyl)phenyl)pyrrolidin-2-yl)acetonitrile: 2A was prepared from ((2S,4R)-4-(benzyloxy)pyrrolidin-2-yl)methanol following the procedure of Example 1. LC-MS Anal. Calc'd C₃₄H₃₃FN₂O₂: 520.64. found [M+H] 521.4.

2B. Methyl 2-((2S,4R)-4-(benzyloxy)-1-(4-((2′-fluoro-5′-methoxy-3-methylbiphenyl-4-yl)methyl)phenyl)pyrrolidin-2-yl)acetate: A ˜3 M solution of HCl in MeOH/CH₂Cl₂/MeOAc was prepared by adding AcCl (13.6 mL, 50.6 mmol) slowly to a solution of CH₂Cl₂ (6 mL) and MeOH (10 mL) at 0° C. After the addition, the reaction was sealed and allowed to stand at rt for 1 h. To a flask with 2A (300 mg, 0.576 mmol) was added the prepared HCl solution (9.60 mL, 28.8 mmol). The reaction was stirred at rt overnight and then concentrated. The crude product was purified by silica chromatography to give 2B (150 mg, 0.271 mmol, 47% yield). LC-MS Anal. Calc'd C₃₅H₃₆FNO₄: 553.66. found [M+H] 554.4.

2C. Methyl 2-((2S,4R)-1-(4-((2′-fluoro-5′-methoxy-3-methylbiphenyl-4-yl)methyl)phenyl)-4-hydroxypyrrolidin-2-yl)acetate: To a flask with 2B (13 2 mg, 0.238 mmol) in MeOH (5 mL) and THF (0.25 mL) was added 20% PdOH₂/C (67.0 mg, 0.095 mmol). The reaction was stirred under H₂ (1 atm) overnight. The reaction mixture was filtered and concentrated. The crude product was purified by silica chromatography to give 2C (57 mg, 0.12 mmol, 52% yield). LC-MS Anal. Calc'd C₂₈H₃₀FNO₄: 463.54. found [M+H] 464.4.

2D. Methyl 2-(4-cyano-1-(4-((2′-fluoro-5′-methoxy-3-methylbiphenyl-4-yl)methyl)phenyl)pyrrolidin-2-yl)acetate: To a solution of 2C (57 mg, 0.12 mmol) in CH₂Cl₂ (2 mL) at 0° C. was added TEA (0.034 mL, 0.25 mmol) and then MsCl (0.014 mL, 0.18 mmol). The reaction was stirred at 0° C. for 25 min. The reaction mixture was diluted with CH₂Cl₂, washed with water and brine, dried (MgSO₄), and concentrated. To the crude mesylate in DMSO (1 mL) was added NaCN (18.1 mg, 0.369 mmol). The reaction mixture was heated to 55° C. overnight. Additional NaCN (18 mg) was added and the reaction mixture was stirred at 60° C. for 6 h. The reaction mixture was diluted with EtOAc, washed with water and brine, dried (Na₂SO₄), and concentrated. The crude product was purified by silica chromatography to give 2D (24 mg, 0.051 mmol, 41% yield) as a colorless oil. LC-MS Anal. Calc'd C₂₉H₂₉FN₂O₃: 472.55. found [M+H] 473.3.

Example 2 (white powder, 10.0 mg) was prepared from 2D following the procedure for Example 16. LC-MS Anal. Calc'd for C₂₈H₂₇FN₂O₃: 458.53. found [M+H] 459.3. ¹H NMR (400 MHz, CD₃CN) δ 7.28-7.43 (2H, m), 6.94-7.23 (5H, m), 6.82-6.93 (1H, m), 6.62 (2H, d), 4.08-4.26 (2H, m), 3.92 (2H, s), 3.80 (3H, s), 3.63-3.74 (1H, m), 3.24-3.58 (2H, m), 2.34-2.93 (3H, m), 2.30 (3H, s), 2.17 (1H, m). Analytical HPLC: RT=11.8 min, HI: 98.0%. hGPR40 EC₅₀=270 nM.

Example 3 2-((2R,4S)-4-Cyclohexyl-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)pyrrolidin-2-yl)acetic acid, HCl

Example 3 was prepared from (2R,4S)-4-cyclohexylpyrrolidine-2-carboxylic acid and 1F following the procedure of Example 1. LC-MS Anal. Calc'd C₃₃H₃₈FNO₃: 515.66. found [M+H] 516.0. ¹H NMR (400 MHz, CD₃CN) δ 7.72 (br. s., 2H), 7.43-7.28 (m, 4H), 7.21 (d, J=7.8 Hz, 1H), 7.11 (dd, J=10.4, 9.1 Hz, 1H), 6.99 (dd, J=6.4, 3.2 Hz, 1H), 6.88 (dt, J=8.9, 3.5 Hz, 1H), 4.06 (s, 2H), 3.80 (s, 3H), 3.71-3.62 (m, 1H), 3.51 (d, J=10.1 Hz, 2H), 3.29 (br. s., 1H), 3.04 (br. s., 1H), 2.36-2.19 (m, 5H), 1.76-1.61 (m, 5H), 1.43 (q, J=12.5 Hz, 1H), 1.30-0.98 (m, 6H). Analytical HPLC: RT=10.3 min, HI: 97.3%. hGPR40 EC₅₀=13 nM.

Example 4 2-((2R,4S)-4-([1,1′-Biphenyl]-4-yl)-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)pyrrolidin-2-yl)acetic acid, HCl

4A. (2S,4R)-1-Benzyl 2-methyl 4-([1,1′-biphenyl]-4-yl)-4-hydroxypyrrolidine-1,2-dicarboxylate: To a solution of (S)-1-benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (8.05 g, 29.0 mmol) in toluene (300 mL) at 0° C. was added 4-biphenylmagnesium bromide (0.5 M in THF) (104 mL, 52.2 mmol) dropwise. The light yellow solution was stirred at this temperature for 1 h. The reaction was quenched with sat. aq. NH₄Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, filtered, concentrated. The residue was purified by silica chromatography and then recrystallized from EtOAc/hexanes to provide 4A (7.29 g, 16.9 mmol, 49% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.65-7.52 (m, 4H), 7.45 (t, J=7.6 Hz, 2H), 7.42-7.27 (m, 8H), 5.28-5.05 (m, 2H), 4.72-4.49 (m, 1H), 4.16-4.00 (m, 1H), 3.93-3.64 (m, 4H), 2.90-2.76 (m, 1H), 2.54 (ddd, J=13.1, 8.9, 1.8 Hz, 1H).

4B. (2R,4S)-1-tert-Butyl 2-methyl 4-([1,1′-biphenyl]-4-yl)pyrrolidine-1,2-dicarboxylate: A solution of 4A (119 mg, 0.275 mmol), BOC₂O (70 μL, 0.30 mmol), and palladium hydroxide on carbon (38.6 mg, 0.275 mmol) in MeOH (2.8 mL) were stirred under H₂ (3 atm) for 4 days. A small amount of EtOAc was added to homogenize the reaction mixture. The reaction mixture was filtered though a pad of CELITE® and rinsed with EtOAc. The reaction mixture was concentrated to give 4B (100 mg, 0.262 mmol, 95% yield) as a colorless oil, which was used without further purification. LC-MS Anal. Calc'd C₂₃H₂₇NO₄: 381.47. found [M+H] 382.0.

Example 4 was prepared from 4B following the procedure of Example 1. LC-MS Anal. Calc'd C₃₉H₃₆FNO₃: 585.71. found [M+H] 586.2. ¹H NMR (500 MHz, methanol-d₄) δ 7.62-7.57 (m, 4H), 7.47-7.40 (m, 4H), 7.35-7.28 (m, 3H), 7.19 (d, J=8.0 Hz, 1H), 7.15 (d, J=8.3 Hz, 2H), 7.08 (dd, J=10.2, 8.8 Hz, 1H), 6.97-6.91 (m, 3H), 6.87 (dt, J=8.9, 3.5 Hz, 1H), 4.38 (br. s., 1H), 3.98 (s, 2H), 3.97-3.91 (m, 1H), 3.83-3.80 (m, 3H), 3.80-3.75 (m, 1H), 3.44-3.37 (m, 1H), 2.85 (dd, J=15.7, 3.3 Hz, 1H), 2.57 (dd, J=15.7, 9.6 Hz, 1H), 2.52-2.42 (m, 1H), 2.36 (ddd, J=12.7, 7.6, 3.2 Hz, 1H), 2.28 (s, 3H). Analytical HPLC: RT=12.9 min, HI: 92.6%. hGPR40 EC₅₀=210 nM.

Example 5 2-((2R,4R)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-phenylpyrrolidin-2-yl)acetic acid

Example 5 was prepared from (2R,4R)-4-phenylpyrrolidine-2-carboxylic acid hydrochloride following the procedure of Example 1. LC-MS Anal. Calc'd C₃₃H₃₂FNO₃: 509.61. found [M+H] 510.0. ¹H NMR (400 MHz, CDCl₃) δ 7.39-7.25 (m, 8H), 7.23-7.10 (m, 4H), 7.08-7.00 (m, 1H), 6.93 (dd, J=6.0, 3.3 Hz, 1H), 6.81 (dt, J=9.1, 3.4 Hz, 1H), 4.31 (br. s., 1H), 4.07 (br. s., 1H), 3.99 (s, 2H), 3.95-3.86 (m, 1H), 3.81 (s, 3H), 3.33 (t, J=9.6 Hz, 1H), 2.96 (br. s., 2H), 2.60-2.45 (m, 2H), 2.29 (s, 3H). Analytical HPLC: RT=13.9 min, HI: 96.5%. hGPR40 EC₅₀=130 nM.

Example 6 2-((2R,4R)-4-([1,1′-Biphenyl]-4-yl)-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-methoxypyrrolidin-2-yl)acetic acid, HCl

6A. (2R,4R)-Benzyl 4-([1,1′-biphenyl]-4-yl)-2-(hydroxymethyl)-4-methoxypyrrolidine-1-carboxylate: To a solution of 4A (8.08 g, 18.7 mmol) in DMF (150 mL) at 0° C. was added 95% NaH (0.520 g, 20.6 mmol). The reaction mixture was stirred for 30 min. Dimethyl sulfate (1.9 mL, 21 mmol) was added dropwise at 0° C. The reaction mixture was warmed to rt and stirred for 2 h. The reaction was quenched with 5% aq. citric acid and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO₄, and concentrated. The residue was purified by silica chromatography to yield (2R,4R)-1-benzyl 2-methyl 4-([1,1′-biphenyl]-4-yl)-4-methoxypyrrolidine-1,2-dicarboxylate (1.35 g, 3.03 mmol, 16% yield) and (2S,4R)-1-benzyl 2-methyl 4-([1,1′-biphenyl]-4-yl)-4-methoxypyrrolidine-1,2-dicarboxylate (1.45 g), which was recrystallized from MeOH (10 mL) to yield 6A (1.20 g, 2.69 mmol, 14% yield) as a white solid.

Example 6 was prepared from 6A following the procedure of Example 1. LC-MS Anal. Calc'd C₄₀H₃₈FNO₄: 615.73. found [M+] 616.1. ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.32 (m, 12H), 7.26 (s, 3H), 7.17 (d, J=6.6 Hz, 1H), 7.06 (t, J=9.3 Hz, 1H), 6.94 (dd, J=5.8, 3.0 Hz, 1H), 6.87-6.76 (m, 1H), 4.49-4.25 (m, 2H), 4.03 (br. s., 2H), 3.82 (s, 4H), 3.57-2.99 (m, 6H), 2.61 (br. s., 1H), 2.30 (s, 3H). Analytical HPLC: RT=13.9 min, HI: 96.5%. hGPR40 EC₅₀=77 nM.

Example 7 2-((2R,4R)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(2-methoxyethoxy)pyrrolidin-2-yl)acetic acid, HCl

7A. (4R)-1-tert-Butyl 2-methyl 4-(2-methoxyethoxy)pyrrolidine-1,2-dicarboxylate: To a solution of (2R,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (0.500 g, 2.04 mmol) in THF (8.2 mL) at 0° C. under argon was added 95% NaH (0.108 g, 4.28 mmol). The reaction mixture was warmed to rt and stirred for 15 min. The reaction mixture was cooled to 0° C., 1-bromo-2-methoxyethane (0.62 g, 4.5 mmol) was added, and the reaction mixture was warmed to rt and stirred for 72 h. The reaction was quenched with sat. aq. NH₄Cl (5 mL) and extracted with EtOAc/Et₂O (1:1 v/v, 3×5 mL). The combined organic layers were washed with water (2×5 mL), brine (5 mL), dried (Na₂SO₄), and concentrated. The crude product was purified by silica chromatography to give 7A (0.128 g, 0.423 mmol, 21% yield) as a colorless oil. LC-MS Anal. Calc'd C₁₄H₂₅NO₆: 303.35. found [M+H-Boc] 204.0.

Example 7 was prepared from 7A following the procedure of Example 1. LC-MS Anal. Calc'd C₃₀H₃₄FNO₅: 507.59. found [M+H] 508.2. ¹H NMR (500 MHz, methanol-d₄) δ 7.37-7.25 (m, 6H), 7.21 (d, J=8.0 Hz, 1H), 7.08 (dd, J=10.2, 8.8 Hz, 1H), 6.94 (dd, J=6.3, 3.0 Hz, 1H), 6.88 (dt, J=8.8, 3.4 Hz, 1H), 4.43 (br. s., 1H), 4.35-4.25 (m, 1H), 4.07 (s, 2H), 3.88 (d, J=12.1 Hz, 1H), 3.81 (s, 3H), 3.76 (dd, J=12.1, 5.2 Hz, 1H), 3.69-3.64 (m, 2H), 3.61-3.57 (m, 2H), 3.40 (s, 3H), 2.87-2.73 (m, 3H), 2.27 (s, 3H), 2.13 (ddd, J=14.9, 5.8, 1.2 Hz, 1H). Analytical HPLC: RT=12.9 min, HI: 99.0%. hGPR40 EC₅₀=240 nM.

Example 8 2-((2R,4S)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(pyridin-3-yl)pyrrolidin-2-yl)acetic acid, HCl

8A. (2R,4R)-tert-Butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate: (2R,4R)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid (6.98 g, 30.2 mmol) was dissolved in anhydrous THF (123 mL) and cooled to −10° C. 4-Methylmorpholine (3.5 mL, 32 mmol) and isobutyl chloroformate (4.2 mL, 32 mmol) were added and the reaction mixture was stirred at −10° C. for 45 min. The reaction mixture was filtered and added dropwise to a solution of NaBH₄ (2.28 g, 60.4 mmol) in water (16 mL) cooled to 0° C. The reaction mixture was stirred for 2 h and slowly warmed to rt. The reaction mixture was quenched with sat. aq. NH₄Cl and the product was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to provide 8A (5.98 g, 27.5 mmol, 91% yield) as a colorless oil, which solidified to a white solid upon standing. LC-MS Anal. Calc'd for C₁₀H₁₉NO₄: 217.26. found [M+H] 218.0. ¹H NMR (500 MHz, CDCl₃) δ 4.35-4.09 (m, 2H), 4.09-3.88 (m, 2H), 3.67-3.33 (m, 3H), 2.44-2.24 (m, 1H), 2.07-1.71 (m, 2H), 1.53-1.40 (m, 9H).

8B. (2R,4R)-tert-Butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylate: To a solution of 8A (3.00 g, 13.8 mmol) in DMF (69 mL) was added TBDPS-Cl (3.9 mL, 15 mmol) and imidazole (1.41 g, 20.7 mmol). The reaction mixture was stirred at rt for 2 h. The reaction mixture was diluted with EtOAc and washed with water (5×). The organic layer was washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to give 8B (2.58 g, 5.66 mmol, 41% yield) as a colorless oil. LC-MS Anal. Calc'd for C₂₆H₃₇NO₄Si: 455.66. found [M+H] 456.1. ¹H NMR (500 MHz, CDCl₃) δ 7.72-7.60 (m, 4H), 7.48-7.34 (m, 6H), 4.78 (d, J=11.0 Hz, 0.5H), 4.50 (d, J=10.2 Hz, 0.5H), 4.37-4.20 (m, 1.5H), 4.01 (br. s, 1H), 3.89 (d, J=9.4 Hz, 0.5H), 3.62-3.42 (m, 3H), 2.45-2.29 (m, 1H), 2.12-1.96 (m, 1H), 1.54-1.43 (s, 4.5H), 1.29 (s, 4.5H), 1.08 (s, 9H).

8C. (R)-tert-Butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-oxopyrrolidine-1-carboxylate: To a solution of 8B (1.59 g, 3.49 mmol) in CH₂Cl₂ (8.7 mL) at 0° C. was added TCCA (0.836 g, 3.49 mmol). After 5 min, TEMPO (5.5 mg, 0.035 mmol) was added. The mixture was stirred at 0° C. for 1 h and then filtered though a pad of CELITE®, rinsing with CH₂Cl₂ (2×10 mL). The organic layer was washed with sat. aq. Na₂CO₃ and brine. The organic layer was dried (Na₂SO₄), filtered and concentrated to afford 8C (1.35 g, 2.83 mmol, 81% yield) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ 7.69-7.50 (m, 4H), 7.49-7.29 (m, 6H), 4.53-4.24 (m, 1H), 4.13-3.77 (m, 3H), 3.61-3.43 (m, 1H), 2.84-2.64 (m, 1H), 2.62-2.45 (m, 1H), 1.56-1.35 (m, 9H), 1.01 (br. s., 9H).

8D. (R)-tert-Butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1-carboxylate: A solution of 8C (0.770 g, 1.70 mmol) in THF (15.7 mL) at −78° C. was added slowly to a stirred solution of 1 M NaHMDS (1.7 mL, 1.7 mmol) in THF (15.7 mL) at −78° C. After 1 h, solution of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (0.667 g, 1.87 mmol) in THF (15.7 mL) cooled to −20° C. was cannulated into the flask and the reaction mixture was allowed to warm slowly to rt. After 4 h, the solvent was removed under reduced pressure. The residue was purified by silica chromatography to give 8D (0.906 g, 1.55 mmol, 91% yield) as a colorless oil. LC-MS Anal. Calc'd for C₂₇H₃₄F₃NO₆SSi: 585.71. found [M+H] 586.0.

8E. (R)-tert-Butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(pyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate: To a solution of 8D (300 mg, 0.512 mmol) and 3-(tributylstannyl)pyridine (226 mg, 0.615 mmol) in THF (2.8 mL) was added CuI (117 mg, 0.615 mmol) followed by LiCl (26.1 mg, 0.615 mmol). The mixture was purged with argon for 10 min. Pd(Ph₃P)₄ (30 mg, 0.026 mmol) was added. The reaction mixture was heated to 65° C. for 4 h. The reaction mixture was diluted with Et₂O (10 mL) and quenched with 5% aq. NH₄OH (2 mL). The aqueous layer was extracted with EtOAc (3×4 mL). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica chromatography to provide 8E (0.1836 g, 0.357 mmol, 70% yield) as a pale yellow oil. LC-MS Anal. Calc'd for C₃₁H₃₈N₂O₃Si: 514.73. found [M+H] 515.2. ¹H NMR (400 MHz, CDCl₃) δ 8.87-8.37 (m, 2H), 7.81-7.52 (m, 5H), 7.46-7.28 (m, 6H), 6.40-6.05 (m, 1H), 4.90-4.38 (m, 3H), 4.90-4.38 (m, 1H), 4.90-4.38 (m, 1H), 4.03-3.68 (m, 1H), 1.64-1.33 (m, 9H), 1.15-0.89 (m, 9H).

8F. (2R,4S)-tert-Butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(pyridin-3-yl)pyrrolidine-1-carboxylate: To a degassed solution of 8E (0.183 g, 0.356 mmol) in MeOH (1.9 mL) was added 10% Pd/C (0.019 g, 0.18 mmol). The mixture was purged with argon and then stirred under H₂ (1 atm) overnight. Additional 10% Pd/C (20 mg, 0.18 mmol) was added and the reaction mixture was stirred under H₂ (1 atm) overnight. The reaction mixture was filtered though a pad of CELITE®, rinsed with MeOH, and concentrated. The residue was dissolved in MeOH (2 mL) and 10% Pd—C (40 mg, 0.36 mmol) was added. The reaction mixture was stirred under H₂ (55 psi) overnight. AcOH (2 mL) was added followed by 10% Pd/C (20 mg, 0.18 mmol). The reaction mixture was stirred under H₂ (55 psi) over the weekend. The reaction mixture was filtered though a pad of CELITE® and rinsed with MeOH. The reaction mixture was concentrated to give 8F (0.100 g, 0.194 mmol, 54% yield) as a yellow oil. LC-MS Anal. Calc'd for C₃₁H₄₀N₂O₃Si: 516.75. found [M+H] 517.3.

8G. (2R,4S)-tert-Butyl 2-(hydroxymethyl)-4-(pyridin-3-yl)pyrrolidine-1-carboxylate: To a solution of 8F (0.100 g, 0.194 mmol) was added a 1 M solution of TBAF in THF (0.39 mL, 0.39 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (5 mL) and washed with sat. aq. NaHCO₃ (3×3 mL). The organic layer was dried (Na₂SO₄), filtered, and concentrated. The residue was purified by silica chromatography to obtain 8G (0.0539 g, 0.194 mmol, 100% yield) as a yellow oil. LC-MS Anal. Calc'd for C₁₅H₂₂N₂O₃: 278.35. found [M+H] 279.1. ¹H NMR (500 MHz, CDCl₃) δ 8.61-8.38 (m, 2H), 7.56 (d, J=7.4 Hz, 1H), 7.28-7.24 (m, 1H), 4.21-3.93 (m, 2H), 3.89-3.62 (m, 2H), 3.40-3.10 (m, 2H), 2.55-2.32 (m, 1H), 1.76-1.58 (m, 1H), 1.47 (s, 9H).

Example 8 was prepared from 8G following the procedure of Example 1. LC-MS Anal. Calc'd for C₃₂H₃₁FN₂O₃: 510.60. found [M+H] 511.2. ¹H NMR (500 MHz, methanol-d₄) δ 8.96 (s, 1H), 8.84-8.72 (m, 2H), 8.12 (dd, J=8.0, 5.8 Hz, 1H), 7.36-7.26 (m, 2H), 7.26-7.13 (m, 5H), 7.08 (t, J=9.6 Hz, 1H), 6.94 (dd, J=6.3, 3.3 Hz, 1H), 6.88 (dt, J=8.8, 3.4 Hz, 1H), 4.50-4.37 (m, 1H), 4.09-3.98 (m, 4H), 3.96-3.87 (m, 1H), 3.81 (s, 3H), 3.02 (dt, J=13.2, 6.3 Hz, 1H), 2.93 (dd, J=16.2, 3.6 Hz, 1H), 2.61 (dd, J=16.2, 8.8 Hz, 1H), 2.37-2.22 (m, 4H). Analytical HPLC: RT=8.3 min, HI: 95.2%. hGPR40 EC₅₀=94 nM.

Example 9, Isomer 1, Isomer 2, Isomer 3, and Isomer 4 2-(1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(3-methylisoxazol-5-yl)pyrrolidin-2-yl)acetic acid, HCl

9A. Methyl 1-(4-bromophenyl)-5-oxopyrrolidine-3-carboxylate: 4-Bromoaniline (5.16 g, 30.0 mmol) and 1-(4-bromophenyl)-5-oxopyrrolidine-3-carboxylic acid were added to a flask and mixed well. The mixture was stirred and heated to 130° C. for 20 min. After 18 min, a solid formed and stirring ceased. MeOH (45 mL) was added to the crude 1-(4-bromophenyl)-5-oxopyrrolidine-3-carboxylic acid (8.52 g, 30 mmol). To this reaction mixture H₂SO₄ (1.0 mL, 19 mmol) was added dropwise. The reaction mixture was stirred at rt for 3 h 15 min. Most of the MeOH was evaporated. The reaction mixture was diluted with EtOAc, washed with water and brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to afford 9A (7.43 g, 24.9 mmol, 83% yield) as an off-white solid. LC-MS Anal. Calc'd for C₁₂H₁₂BrNO₃: 298.13. found [M+H] 299.8. ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.41 (m, 4H), 4.15-4.06 (m, 1H), 4.05-3.96 (m, 1H), 3.78 (s, 3H), 3.45-3.31 (m, 1H), 3.01-2.81 (m, 2H).

9B. 1-(4-Bromophenyl)-4-(3-methylisoxazol-5-yl)pyrrolidin-2-one: A solution of n-BuLi (8.0 mL, 20 mmol) (2.5 M in pentane) was added dropwise to a solution of acetoxime (0.731 g, 10.0 mmol) in THF (23 mL) at 0° C. and the resulting mixture warmed to rt and stirred at rt for 35 min. A solution of 9A (1.49 g, 5.00 mmol) in THF (5.2 mL) was added dropwise over 15 min. The reaction mixture was stirred at rt for 1 h. The mixture was cooled to −5° C., and ice-cold 1 N aq. HCl (20 mL) was carefully added. The organic layer was separated and the aqueous layer neutralized with 1 N aq. HCl to pH ˜7. The product was extracted with EtOAc (3×). The combined organic layers were dried (MgSO₄) and concentrated. The crude product was purified by silica chromatography to give (Z)-1-(4-bromophenyl)-4-(3-(hydroxyimino)butanoyl)pyrrolidin-2-one 700 mg, ˜80% pure. To a solution of the crude product in CH₂Cl₂ (20 mL) at 0° C. was added NEt₃ (0.40 mL, 2.9 mmol) followed by the dropwise addition of MsCl (0.21 mL, 2.7 mmol). The reaction mixture was stirred at rt for 3.5 h. The mixture was concentrated, diluted with EtOAc, washed with water and brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to give 9B (330 mg, 1.03 mmol, 21% yield) as a gum. LC-MS Anal. Calc'd for C₁₄H₁₃BrN₂O₂: 321.17. found [M+H] 322.8. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 4H), 5.99 (s, 1H), 4.16 (dd, J=9.6, 8.0 Hz, 1H), 4.01-3.93 (m, 1H), 3.91-3.76 (m, 1H), 3.01 (dd, J=17.0, 8.8 Hz, 1H), 2.83 (dd, J=17.0, 7.7 Hz, 1H), 2.29 (s, 3H).

9C. 1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl) phenyl)-4-(3-methylisoxazol-5-yl)pyrrolidin-2-one: 9C was prepared from 9B following the procedure of Example 1. LC-MS Anal. Calc'd for C₂₉H₂₇FN₂O₃: 470.54. found [M+H] 471.1. ¹H NMR (400 MHz, CDCl₃) δ 7.58-7.48 (m, 2H), 7.39-7.29 (m, 2H), 7.20-7.12 (m, 3H), 7.05 (dd, J=9.9, 8.8 Hz, 1H), 6.93 (dd, J=6.0, 3.3 Hz, 1H), 6.80 (dt, J=8.8, 3.6 Hz, 1H), 5.05 (d, J=1.1 Hz, 1H), 4.07 (dd, J=9.6, 7.4 Hz, 1H), 3.99 (s, 2H), 3.89 (t, J=9.1 Hz, 1H), 3.82 (s, 3H), 3.37-3.23 (m, 1H), 2.90 (dd, J=17.0, 8.2 Hz, 1H), 2.75 (dd, J=17.0, 8.8 Hz, 1H), 2.29 (s, 3H), 1.97 (s, 3H).

9D. Ethyl 2-(1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(3-methylisoxazol-5-yl)pyrrolidin-2-yl)acetate: To a solution of 9C (128 mg, 0.272 mmol) in THF (2.7 mL) at −78° C., was added a 1 M solution of lithium triethylborohydride in THF (0.98 mL, 0.98 mmol). The reaction mixture was stirred at −78° C. for 1 h 40 min. The reaction mixture was quenched with concentrated aq. NaHCO₃ (1.4 mL), warmed to 0° C. and H₂O₂ (30% in water, 0.7 mL) was added dropwise. The mixture was stirred at 0° C. for 20 min, diluted with EtOAc, washed with sat. aq. NaHCO₃, water, and brine, and dried (MgSO₄). The solution was passed though a silica gel pad, the pad was rinsed with EtOAc, and the organic layer was concentrated. The crude 1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(3-methylisoxazol-5-yl)pyrrolidin-2-ol was used for next reaction directly. To a solution of 60% NaH (82 mg, 2.0 mmol) in THF (2 mL) was added triethyl phosphonoacetate (0.44 mL, 2.2 mmol) dropwise. The reaction mixture was stirred at rt for 30 min. 1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(3-methylisoxazol-5-yl)pyrrolidin-2-ol (129 mg, 0.272 mmol) in THF (1.0 mL) was added. The reaction mixture was stirred at 60° C. for 12 h. The reaction mixture was cooled to rt, quenched with sat. aq. NH₄Cl, diluted with EtOAc, washed with water and brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to give 9D (25 mg, 0.046 mmol, 17% yield). LC-MS Anal. Calc'd for C₃₃H₃₅FN₂O₄: 542.64. found [M+H] 543.0.

Example 9, Isomer 1, Isomer 2, Isomer 3, and Isomer 4: To a solution of 9D (30 mg, 0.055 mmol) in THF (1.5 mL) and MeOH (1.0 mL) was added a solution of LiOH (7.6 mg, 0.32 mmol) in water (0.50 mL) dropwise. The reaction mixture was stirred at rt for 3.5 h. The reaction mixture was concentrated, cooled in an ice-water bath, and 1 N aq. HCl (1 mL) was added. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO₄), and concentrated. The residue was dissolved in CH₃CN (3 mL) and treated with 1 N aq. (HCl 1 mL) and lyophilized to give 26.9 mg of the product as a light yellow solid. The isomers were separated by chiral SFC to give single isomers. The products were treated with CH₃CN/1 N HCl in Et₂O and concentrated. Then the products were treated with CH₃CN/1 N aq. HCl and lyophilized to give Example 9 Isomer 1, Isomer 2, Isomer 3, and Isomer 4 as HCl salts. Example 9, Isomer 1 (9.1 mg, 0.016 mmol, 29% yield) was isolated as a light yellow solid. LC-MS Anal. Calc'd for C₃₁H₃₁FN₂O₄: 514.59. found [M+] 514.9. ¹H NMR (400 MHz, acetonitrile-d₃) δ 7.75 (d, J=8.2 Hz, 2H), 7.43-7.32 (m, 4H), 7.21 (d, J=8.2 Hz, 1H), 7.11 (dd, J=10.4, 8.8 Hz, 1H), 6.99 (dd, J=6.0, 3.3 Hz, 1H), 6.88 (dt, J=9.1, 3.4 Hz, 1H), 6.33 (s, 1H), 4.37-4.23 (m, 1H), 4.20-4.01 (m, 4H), 3.95-3.84 (m, 1H), 3.80 (s, 3H), 3.08 (dd, J=17.0, 8.8 Hz, 1H), 2.97-2.88 (m, 1H), 2.84 (dd, J=16.8, 4.7 Hz, 1H), 2.46-2.32 (m, 1H), 2.29 (s, 3H), 2.23 (s, 3H). Analytical HPLC: RT=11.4 min, HI: 96.8%. hGPR40 EC₅₀=150 nM. Example 9, Isomer 2 (2.6 mg, 0.0040 mmol, 7% yield) was isolated as a light yellow solid. LC-MS Anal. Calc'd for C₃₁H₃₁FN₂O₄: 514.59. found [M+] 514.9. ¹H NMR (400 MHz, acetonitrile-d₃) δ 7.48 (d, J=7.1 Hz, 2H), 7.38 (s, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.29 (d, J=8.2 Hz, 2H), 7.21 (d, J=7.7 Hz, 1H), 7.11 (dd, J=10.4, 8.8 Hz, 1H), 6.99 (dd, J=6.0, 3.3 Hz, 1H), 6.88 (dt, J=8.9, 3.5 Hz, 1H), 6.17 (s, 1H), 4.35-4.22 (m, 1H), 4.19-4.06 (m, 2H), 4.04 (s, 2H), 3.80 (s, 3H), 3.57 (d, J=12.6 Hz, 1H), 2.93 (dd, J=16.8, 9.1 Hz, 1H), 2.82 (dd, J=17.0, 4.4 Hz, 1H), 2.67-2.58 (m, 1H), 2.57-2.46 (m, 1H), 2.29 (s, 3H), 2.24 (s, 3H). Analytical HPLC: RT=11.6 min, HI: 84.0%. hGPR40 EC₅₀=2200 nM. Example 9, Isomer 3 (1.9 mg, 0.0032 mmol, 6% yield) was isolated as a light yellow solid. LC-MS Anal. Calc'd for C₃₁H₃₁FN₂O₄: 514.59. found [M+] 514.9. ¹H NMR (400 MHz, acetonitrile-d₃) δ 7.41-7.29 (m, 4H), 7.23 (dd, J=17.0, 8.2 Hz, 2H), 7.11 (dd, J=10.4, 9.3 Hz, 1H), 6.99 (dd, J=6.6, 3.3 Hz, 1H), 6.88 (dt, J=8.9, 3.5 Hz, 1H), 6.15 (s, 1H), 4.31-4.22 (m, 1H), 4.17 (d, J=6.0 Hz, 1H), 4.10-4.04 (m, 1H), 4.02 (s, 2H), 3.80 (s, 3H), 3.57-3.45 (m, 1H), 2.82 (d, J=5.5 Hz, 2H), 2.65-2.42 (m, 3H), 2.29 (s, 3H), 2.23 (s, 3H). Analytical HPLC: RT=11.6 min, HI: 92.0%. hGPR40 EC₅₀=1400 nM. Example 9, Isomer 4 (9.1 mg, 0016 mmol, 29% yield) was isolated as a light yellow solid. LC-MS Anal. Calc'd for C₃₁H₃₁FN₂O₄: 514.59. found [M+] 514.9. ¹H NMR (400 MHz, acetonitrile-d₃) δ 7.72 (d, J=8.2 Hz, 2H), 7.42-7.29 (m, 4H), 7.21 (d, J=8.2 Hz, 1H), 7.11 (dd, J=10.2, 9.1 Hz, 1H), 6.99 (dd, J=6.3, 3.0 Hz, 1H), 6.88 (dt, J=8.8, 3.6 Hz, 1H), 6.33 (s, 1H), 4.35-4.23 (m, 1H), 4.19-3.99 (m, 4H), 3.93-3.84 (m, 1H), 3.80 (s, 3H), 3.05 (dd, J=16.8, 8.5 Hz, 1H), 2.97-2.88 (m, 1H), 2.84 (dd, J=16.8, 4.7 Hz, 1H), 2.43-2.33 (m, 1H), 2.29 (s, 3H), 2.23 (s, 3H). Analytical HPLC: RT=11.4 min, HI: 96.2%. hGPR40 EC₅₀=3500 nM.

Example 10 2-((2R,4S)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(pyridin-2-yl)pyrrolidin-2-yl)acetic acid, HCl

10A. (R)-tert-Butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate: To a solution of 8D (566 mg, 0.967 mmol) and 2-(tributylstannyl)pyridine (427 mg, 1.16 mmol) in THF (5.4 mL) in a microwave vial was added CuI (221 mg, 1.16 mmol) followed by LiCl (49 mg, 1.2 mmol). The mixture was purged with argon for 10 min and then Pd(Ph₃P)₄ (56 mg, 0.048 mmol) was added. The vial was sealed and heated to 65° C. for 4 h. The reaction mixture was diluted with Et₂O (10 mL) and quenched with 5% aq. NH₄OH (2 mL). The aqueous layer was extracted with EtOAc (3×4 mL). The combined organic layers were washed with brine (5 mL), dried (Na₂SO₄), and concentrated. The crude product was purified by silica chromatography to provide 10A (0.404 g, 0.785 mmol, 81% yield) as a yellow oil. LC-MS Anal. Calc'd for C₃₁H₃₈N₂O₃Si: 514.73. found [M+H] 515.3. ¹H NMR (400 MHz, CDCl₃) δ 8.62 (br. s., 1H), 7.84-7.54 (m, 5H), 7.49-7.27 (m, 7H), 7.19 (ddd, J=7.5, 4.9, 1.0 Hz, 1H), 6.77-6.29 (m, 1H), 4.97-4.46 (m, 3H), 4.20-3.70 (m, 2H), 1.72-1.31 (m, 9H), 1.01 (d, J=3.0 Hz, 9H).

10B. (2R,4S)-tert-Butyl 2-(((tert-butyldiphenylsilyl)oxy)methyl)-4-(pyridin-2-yl)pyrrolidine-1-carboxylate: To a degassed solution of 10A (0.200 g, 0.389 mmol) in MeOH (1.94 mL) and AcOH (1.9 mL) was added 10% Pd/C (0.041 g, 0.39 mmol). The mixture was purged with argon before charging the vessel with H₂ (55 psi) and stirring overnight. The reaction mixture was filtered through a pad of CELITE® and rinsed with MeOH. The solvent was removed to give 10B (0.200 g, 0.387 mmol, 100% yield) and the residue was used in the next step without further purification. LC-MS Anal. Calc'd for C₃₁H₄₀N₂O₃Si: 516.75. found [M+H] 517.3.

Example 10 was prepared from 10B following the procedure of Example 1. LC-MS Anal. Calc'd for C₃₂H₃₁FN₂O₃: 510.60. found [M+H] 511.0. ¹H NMR (400 MHz, acetonitrile-d₃) δ 8.68-8.58 (m, 1H), 8.40 (td, J=8.0, 1.6 Hz, 1H), 7.91 (d, J=8.2 Hz, 1H), 7.88-7.80 (m, 1H), 7.48-7.28 (m, 4H), 7.22 (t, J=7.1 Hz, 3H), 7.11 (dd, J=10.4, 8.8 Hz, 1H), 6.99 (dd, J=6.6, 3.3 Hz, 1H), 6.92-6.83 (m, 1H), 4.68 (br. s., 1H), 4.48 (quin, J=8.9 Hz, 1H), 4.10-4.02 (m, 1H), 4.00 (s, 2H), 3.80 (s, 3H), 2.89-2.68 (m, 3H), 2.59 (ddd, J=13.3, 8.7, 4.9 Hz, 1H), 2.31 (s, 3H), 1.92-1.88 (m, 1H). Analytical HPLC: RT=8.9 min, HI: 92.0%. hGPR40 EC₅₀=1400 nM.

Example 11, Isomer 1 and Isomer 2 2-(1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(isoxazol-3-yl)pyrrolidin-2-yl)acetic acid, HCl

11A. 1-(4-Bromophenyl)-1H-pyrrol-2(5H)-one: To a solution of 4-bromoaniline (7.74 g, 45.0 mmol) and 2,5-dimethoxy-2,5-dihydrofuran (11.7 g, 90.0 mmol) in CH₃CN (225 mL) was added 2.5 M aq. HCl (180 mL, 72.0 mmol) in several portions. The reaction mixture was stirred at rt for 5.5 h. The reaction mixture was quenched with a solution of NaHCO₃ (12.1 g, 144 mmol) in water (200 mL) slowly in portions with stirring, and then the reaction mixture was concentrated to remove the CH₃CN. The residue was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to give 11A (2.8 g, 10.9 mmol, 24% yield, 93% purity) as a brown solid. LC-MS Anal. Calc'd for C₁₀H₈BrNO: 238.08. found [M+H] 239.8. ¹H NMR (400 MHz, CDCl₃) δ 7.70-7.56 (m, 2H), 7.53-7.41 (m, 2H), 7.18 (dt, J=6.0, 1.9 Hz, 1H), 6.26 (dt, J=6.0, 1.6 Hz, 1H), 4.41 (t, J=1.6 Hz, 2H).

11B. 1-(4-Bromophenyl)-4-(nitromethyl)pyrrolidin-2-one: To a solution of 11A (1.43 g, 6.01 mmol) in nitromethane (9.0 mL, 170 mmol) at rt was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 mL, 6.0 mmol) dropwise over 10 min. The reaction mixture was stirred at rt for 21 h. The mixture was concentrated, diluted with EtOAc, washed with 1 N aq. HCl (10 mL), water, and brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to give 11B (1.06 g, 3.54 mmol, 59% yield) as an off-white solid. LC-MS Anal. Calc'd for C₁₁H₁₁BrN₂O₃: 299.12. found [M+H] 300.8. ¹H NMR (400 MHz, CDCl₃) δ 7.48 (s, 4H), 4.65-4.43 (m, 2H), 4.10 (dd, J=10.4, 7.7 Hz, 1H), 3.70 (dd, J=9.9, 6.0 Hz, 1H), 3.36-3.21 (m, 1H), 2.95-2.81 (m, 1H), 2.43 (dd, J=17.0, 7.1 Hz, 1H).

11C. 1-(4-Bromophenyl)-4-(isoxazol-3-yl)pyrrolidin-2-one: To a solution of 11B (452 mg, 1.51 mmol), a 1 M solution of vinyl bromide (12.1 mL, 12.1 mmol) in THF, and 1,4-phenylene diisocyanate (847 mg, 5.29 mmol) in THF (2 mL) was added NEt₃ (0.37 mL, 2.6 mmol). The reaction mixture was heated to 80° C. for 11 h. The mixture was diluted with EtOAc (30 mL) and the solid was removed by filtration. The filtrate was concentrated. The crude product was purified by silica chromatography to give 11C (340 mg, 1.11 mmol, 73% yield) as an off-white solid. LC-MS Anal. Calc'd for C₁₃H₁₁BrN₂O₂: 307.14. found [M+H] 308.8. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (d, J=1.6 Hz, 1H), 7.55-7.44 (m, 4H), 6.32 (d, J=1.6 Hz, 1H), 4.27-4.13 (m, 1H), 4.05 (dd, J=9.6, 6.9 Hz, 1H), 3.96-3.79 (m, 1H), 3.15-2.98 (m, 1H), 2.83 (dd, J=17.0, 8.2 Hz, 1H).

11D. Example 11, Isomer 1 and Isomer 2 were prepared from 11C following the procedure of Example 1. Example 11, Isomer 1. LC-MS Anal. Calc'd for C₃₀H₂₉FN₂O₄: 500.56. found [M+H] 501.3. ¹H NMR (400 MHz, acetonitrile-d₃) δ 8.53 (d, J=1.1 Hz, 1H), 7.75 (d, J=8.2 Hz, 2H), 7.39 (s, 1H), 7.36 (d, J=8.2 Hz, 3H), 7.21 (d, J=7.7 Hz, 1H), 7.11 (dd, J=10.4, 8.8 Hz, 1H), 6.99 (dd, J=6.3, 3.0 Hz, 1H), 6.93 (d, J=1.1 Hz, 1H), 6.88 (dt, J=8.9, 3.5 Hz, 1H), 4.39-4.27 (m, 1H), 4.22-4.10 (m, 2H), 4.07 (s, 2H), 3.94-3.84 (m, 1H), 3.80 (s, 3H), 3.07 (dd, J=17.0, 8.8 Hz, 1H), 2.96-2.79 (m, 2H), 2.46-2.33 (m, 1H), 2.29 (s, 3H). Analytical HPLC: RT=10.2 min, HI: 98.7%. hGPR40 EC₅₀=8100 nM. Example 11, Isomer 2. LC-MS Anal. Calc'd for C₃₀H₂₉FN₂O₄: 500.56. found [M+H] 501.3. ¹H NMR (400 MHz, acetonitrile-d₃) δ 8.53 (d, J=1.1 Hz, 1H), 7.76 (d, J=8.2 Hz, 2H), 7.43-7.30 (m, 4H), 7.21 (d, J=7.7 Hz, 1H), 7.15-7.05 (m, 1H), 6.98 (dd, J=6.3, 3.0 Hz, 1H), 6.93 (d, J=1.1 Hz, 1H), 6.88 (dt, J=8.8, 3.3 Hz, 1H), 4.40-4.26 (m, 1H), 4.24-4.10 (m, 2H), 4.07 (s, 2H), 3.97-3.84 (m, 1H), 3.80 (s, 3H), 3.08 (dd, J=17.0, 8.8 Hz, 1H), 2.97-2.78 (m, 2H), 2.47-2.31 (m, 1H), 2.28 (s, 3H). Analytical HPLC: RT=10.2 min, HI: 97.7%. hGPR40 EC₅₀=550 nM.

Example 12, Isomer 1 2-((2R,4S)-4-(3-Chlorophenyl)-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)pyrrolidin-2-yl)acetic acid, HCl

and

Example 12, Isomer 2 2-((2R,4R)-4-(3-Chlorophenyl)-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)pyrrolidin-2-yl)acetic acid, HCl

12A. (R)-1-Benzyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate: To a solution of (2R,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (16.7 g, 59.7 mmol) in CH₂Cl₂ (149 mL) was added TCCA (13.9 g, 59.7 mmol) followed by the addition of TEMPO (0.093 g, 0.60 mmol). The reaction mixture was warmed to rt and stirred for 15 min. The reaction mixture was filtered and washed with sat. aq. Na₂CO₃, 0.1 M aq. HCl, and brine. The organic layer was dried (MgSO₄) and concentrated. The material was filtered though a plug of silica gel to obtain 12A (12.6 g, 45.3 mmol, 76% yield) as a colorless oil, which solidified upon standing to a pale yellow solid. LC-MS Anal. Calc'd for C₁₄H₁₅NO₅: 277.27. found [M+H] 278.0. ¹H NMR (500 MHz, CDCl₃) δ 7.43-7.28 (m, 5H), 5.27-5.20 (m, 1H), 5.19-5.08 (m, 1H), 4.92-4.78 (m, 1H), 4.07-3.88 (m, 2H), 3.81-3.56 (m, 3H), 3.03-2.87 (m, 1H), 2.61 (dd, J=18.8, 2.6 Hz, 1H).

12B. (R)-7-Benzyl 8-methyl 1,4-dioxa-7-azaspiro[4.4]nonane-7,8-dicarboxylate: 12A (12.6 g, 45.3 mmol) and ethane-1,2-diol (2.5 mL, 45 mmol) were dissolved in toluene (450 mL). TsOH (1.01 g, 5.89 mmol) was added. The resulting mixture was heated to reflux for 18 h. The reaction mixture was cooled to rt, poured into ice-water, extracted with EtOAc (3×), washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to provide 12B (8.58 g, 26.7 mmol, 59% yield) as a pale yellow oil, which solidified upon standing. LC-MS Anal. Calc'd for C₁₆H₁₉NO₆: 321.33. found [M+H] 322.0. ¹H NMR (400 MHz, CDCl₃) δ 7.42-7.27 (m, 5H), 5.25-4.99 (m, 2H), 4.60-4.42 (m, 1H), 4.02-3.87 (m, 4H), 3.82-3.53 (m, 5H), 2.48-2.34 (m, 1H), 2.29-2.17 (m, 1H).

12C. (R)-Benzyl 8-(hydroxymethyl)-1,4-dioxa-7-azaspiro[4.4]nonane-7-carboxylate: To a solution of 12B (8.58 g, 26.7 mmol) in THF (89 mL) at 0° C. was added a 2 M solution of LiBH₄ (13.3 mL, 27 mmol) in THF. The reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was quenched with sat. aq. NH₄Cl and diluted with EtOAc/water. The layers were separated and the organic layer was washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to give 12C (7.33 g, 25.0 mmol, 94% yield) as a colorless oil. LC-MS Anal. Calc'd for C₁₅H₁₉NO₅: 293.32. found [M+H] 294.1. ¹H NMR (500 MHz, CDCl₃) δ 7.41-7.30 (m, 5H), 5.14 (s, 2H), 4.21-4.14 (m, 1H), 4.03-3.87 (m, 4H), 3.83-3.64 (m, 2H), 3.58 (d, J=11.6 Hz, 1H), 3.47 (d, J=11.6 Hz, 1H), 2.30-2.16 (m, 1H), 1.86 (dd, J=12.9, 6.6 Hz, 1H).

12D. (R)-1,4-Dioxa-7-azaspiro[4.4]nonan-8-ylmethanol: To a solution of 12C (7.33 g, 25.0 mmol) in MeOH (125 mL) was added 10% Pd/C (0.665 g, 1.25 mmol). The reaction mixture was purged with argon (3×) and then with H₂ (3×) and stirred under H₂ (1 atm) overnight. The reaction mixture was filtered and concentrated to provide 12D (4.012 g, 25.2 mmol, 100% yield) as a brown oil. LC-MS Anal. Calc'd for C₇H₁₃NO₃: 159.18. found [M+H] 160.0. ¹H NMR (500 MHz, CDCl₃) δ 3.99-3.85 (m, 4H), 3.63-3.51 (m, 1H), 3.50-3.39 (m, 2H), 2.93 (s, 2H), 2.04 (dd, J=13.6, 7.6 Hz, 1H), 1.76 (dd, J=13.8, 6.9 Hz, 1H).

12E. (R)-2-(7-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)acetic acid: 12E was prepared from 12D following the procedure of Example 1. LC-MS Anal. Calc'd for C₂₉H₃₀FNO₅: 491.55. found [M+H] 492.3.

12F. (R)-2-(1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl) phenyl)-4-oxopyrrolidin-2-yl)acetic acid: A solution of 12E (59.4 mg, 0.121 mmol) and TsOH (28.7 mg, 0.151 mmol) in acetone (1.7 mL) and water (0.73 mL) was heated to 56° C. for 12 h. The reaction mixture was concentrated and purified by RP-Prep. HPLC to provide 12F (28 mg, 0.062 mmol, 51% yield). ¹H NMR (500 MHz, CH₂Cl₂-d₂) δ 7.34 (s, 1H), 7.31 (d, J=7.7 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.12 (d, J=8.5 Hz, 2H), 7.06 (dd, J=10.2, 8.8 Hz, 1H), 6.94 (dd, J=6.5, 3.2 Hz, 1H), 6.82 (dt, J=8.9, 3.5 Hz, 1H), 6.62 (d, J=8.5 Hz, 2H), 4.68 (tt, J=8.8, 2.2 Hz, 1H), 3.95 (s, 2H), 3.81 (s, 3H), 3.76 (d, J=17.9 Hz, 1H), 3.67 (d, J=18.4 Hz, 1H), 2.96 (dd, J=18.4, 8.8 Hz, 1H), 2.86 (dd, J=16.2, 2.8 Hz, 1H), 2.64-2.48 (m, 2H), 2.32 (s, 3H).

12G. 2-((2R,4S)-4-(3-Chlorophenyl)-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-hydroxypyrrolidin-2-yl)acetic acid, HCl: To a suspension of cerium(III) chloride (212 mg, 0.858 mmol) in THF (1.4 mL) at −40° C. was added (3-chlorophenyl)magnesium bromide (1 M in THF) (86 μL, 0.86 mmol) slowly. The mixture was stirred at this temperature for 1.5 h. A solution of 12F (64 mg, 0.14 mmol) in THF (1.4 mL) was added to above mixture slowly. The resulting solution was gradually warmed to rt. The reaction mixture was cooled to −40° C. and (3-chlorophenyl)magnesium bromide (1 M in THF) (28 μL, 0.28 mmol) was added. The reaction mixture was carefully quenched with AcOH and extracted with EtOAc (3×2 mL). The combined organic layers were evaporated. The residue was purified in RP-Prep HPLC to give 12G (13 mg, 0.022 mmol, 15% yield) as a light yellow solid. LC-MS Anal. Calc'd for C₃₃H₃₁ClFNO₄: 560.06. found [M+H] 561.0. ¹H NMR (500 MHz, CDCl₃) δ 7.52 (t, J=1.7 Hz, 1H), 7.41-7.37 (m, 1H), 7.36-7.27 (m, 4H), 7.16 (dd, J=13.3, 8.1 Hz, 3H), 7.05 (dd, J=9.9, 8.8 Hz, 1H), 6.99-6.90 (m, 3H), 6.81 (dt, J=8.9, 3.4 Hz, 1H), 4.44-4.32 (m, 1H), 3.99 (s, 2H), 3.98-3.94 (m, 1H), 3.82 (s, 3H), 3.65 (d, J=11.0 Hz, 1H), 3.16-3.02 (m, 2H), 2.81 (dd, J=14.0, 9.1 Hz, 1H), 2.49-2.40 (m, 1H), 2.30 (s, 3H).

Example 12, Isomer 1 and Isomer 2: To a solution of 12G (13 mg, 0.023 mmol) in CH₂Cl₂ (0.23 mL) was added triethylsilane (37 μL, 0.23 mmol) followed by TFA (18 μL, 0.23 mmol). The mixture was stirred at rt for 6 h. Additional triethylsilane (2 mL) and TFA (0.2 mL) were added and the reaction mixture was heated to 40° C. Additional TFA (0.2 mL) and triethylsilane (0.2 mL) were added. The reaction mixture was cooled to rt and concentrated. The crude product was purified by RP-Prep. HPLC to provide Example 12 as single isomers. Example 12, Isomer 1 (0.73 mg, 0.0012 mmol, 5% yield). LC-MS Anal. Calc'd for C₃₃H₃₁ClFNO₃: 544.06. found [M+] 544.3. ¹H NMR (500 MHz, methanol-d₄) δ 7.36 (s, 1H), 7.33-7.25 (m, 4H), 7.24-7.20 (m, 1H), 7.16 (d, J=7.7 Hz, 1H), 7.11-7.04 (m, 1H), 7.01 (d, J=8.5 Hz, 2H), 6.95 (dd, J=6.3, 3.0 Hz, 1H), 6.85 (dt, J=8.9, 3.4 Hz, 1H), 6.61 (d, J=8.5 Hz, 2H), 4.34-4.22 (m, 1H), 3.92 (s, 2H), 3.81 (s, 4H), 3.75-3.63 (m, 1H), 3.19-3.10 (m, 1H), 2.89-2.77 (m, 2H), 2.39 (dd, J=14.7, 10.6 Hz, 1H), 2.28 (s, 3H), 2.28-2.24 (m, 1H). Analytical HPLC: RT=12.9 min, HI: 95.0%. hGPR40 EC₅₀=160 nM. Example 12, Isomer 2 (0.86 mg, 0.0014 mmol, 6% yield). LC-MS Anal. Calc'd for C₃₃H₃₁ClFNO₃: 544.06. found [M+] 544.3. ¹H NMR (500 MHz, acetonitrile-d₃) δ 7.59-7.26 (m, 10H), 7.22 (d, J=8.0 Hz, 1H), 7.11 (t, J=9.6 Hz, 1H), 6.98 (dd, J=6.3, 3.3 Hz, 1H), 6.88 (dt, J=8.9, 3.3 Hz, 1H), 4.30 (dq, J=11.5, 5.8 Hz, 1H), 4.05 (s, 2H), 3.99-3.83 (m, 3H), 3.79 (s, 3H), 2.91-2.75 (m, 3H), 2.29 (s, 3H), 2.27-2.15 (m, 1H). Analytical HPLC: RT=12.9 min, HI: 95.0%. hGPR40 EC₅₀=10 nM.

Example 13, Isomer 1, and Isomer 2 2-((2R,4S)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(piperidin-1-yl)pyrrolidin-2-yl)acetic acid

and

2-((2R,4R)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(piperidin-1-yl)pyrrolidin-2-yl)acetic acid, diethylamine

To a solution of 12F (40 mg, 0.089 mmol) in CH₂Cl₂ (0.56 mL) and MeOH (0.93 mL) under argon was added piperidine (8.4 mg, 0.098 mmol) and AcOH (5.1 μL, 0.089 mmol), followed by MgSO₄ (150 mg). The mixture was stirred at rt for 2 h. The reaction mixture was cooled to 0° C. and a 1 M solution of sodium cyanoborohydride (98 μL, 0.098 mmol) in THF was added. The mixture was gradually warmed to rt and stirred over the weekend. The reaction mixture was filtered and the solids were washed with MeOH/CH₂Cl₂ (1:1 v/v). The reaction mixture was concentrated and the reside was purified by RP-Prep. HPLC to give the product as a mixture of isomers (17 mg, 0.033 mmol, 37% yield). The products were separated as single isomers by chiral SFC. Example 13, Isomer 1 (light brown solid, 3.0 mg, 0.0048 mmol, 16% yield). LC-MS Anal. Calc'd for C₃₂H₃₇FN₂O₃: 516.65. found [M+H] 517.3. ¹H NMR (500 MHz, methanol-d₄) δ 7.34-7.26 (m, 2H), 7.16 (d, J=7.7 Hz, 1H), 7.10-7.02 (m, 3H), 6.95 (dd, J=6.3, 3.3 Hz, 1H), 6.86 (dt, J=8.9, 3.5 Hz, 1H), 6.64 (d, J=8.5 Hz, 2H), 4.39 (t, J=9.1 Hz, 1H), 4.20-4.12 (m, 1H), 3.94 (s, 2H), 3.87-3.82 (m, 1H), 3.81 (s, 3H), 3.43-3.37 (m, 2H), 2.75 (d, J=13.2 Hz, 1H), 2.49 (dd, J=12.7, 7.2 Hz, 1H), 2.40-2.29 (m, 2H), 2.28 (s, 3H), 1.38-1.22 (m, 6H), 0.98-0.81 (m, 3H). Analytical HPLC: RT=7.5 min, HI: 97.2%. hGPR40 EC₅₀=6700 nM. Example 13, Isomer 2 (light brown solid, 11 mg, 0.018 mmol, 59% yield). LC-MS Anal. Calc'd for C₃₂H₃₇FN₂O₃: 516.65. found [M+H] 517.3. ¹H NMR (500 MHz, methanol-d₄) δ 7.35-7.25 (m, 2H), 7.17 (d, J=8.0 Hz, 1H), 7.13 (d, J=8.5 Hz, 2H), 7.07 (dd, J=10.2, 9.1 Hz, 1H), 6.95 (dd, J=6.3, 3.3 Hz, 1H), 6.90 (d, J=8.5 Hz, 2H), 6.86 (dt, J=9.0, 3.5 Hz, 1H), 4.35-4.23 (m, 1H), 3.98 (s, 2H), 3.96-3.85 (m, 2H), 3.83 (br. s., 1H), 3.80 (s, 3H), 3.70-3.63 (m, 1H), 3.63-3.55 (m, 1H), 3.05 (q, J=7.4 Hz, 6H), 2.97 (dd, J=13.1, 7.0 Hz, 1H), 2.93 (dd, J=16.2, 3.3 Hz, 1H), 2.47 (dd, J=16.2, 9.4 Hz, 1H), 2.27 (s, 3H), 2.20 (dt, J=12.9, 8.8 Hz, 1H), 2.04-1.93 (m, 2H), 1.86 (d, J=11.3 Hz, 3H), 1.62-1.47 (m, 1H), 1.31 (t, J=7.3 Hz, 6H). Analytical HPLC: RT=7.5 min, HI: 97.6%. hGPR40 EC₅₀=2800 nM.

Example 15, Isomer 1 and Isomer 2 2-((2R,4S)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(2-methoxyphenyl)pyrrolidin-2-yl)acetic acid, HCl

and

2-((2R,4R)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(2-methoxyphenyl)pyrrolidin-2-yl)acetic acid, HCl

15A. (R)-(7-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl) phenyl)-1,4-dioxa-7-azaspiro[4.4]nonan-8-yl)methanol: To a vial of 1F (3.38 g, 7.81 mmol), 12D (1.13 g, 7.10 mmol), and NaOH (0.568 g, 14.2 mmol) in n-BuOH (14 mL) was added CuI (0.034 g, 0.177 mmol). The reaction mixture was sealed and heated to 90° C. overnight. The reaction mixture was cooled to rt and quenched with sat. aq. NH₄Cl (14 mL). The product was extracted with CH₂Cl₂ (3×3 mL). The combined organic layers were washed with sat. aq. NH₄Cl (3×10 mL) and brine, dried over Na₂SO₄, and concentrated. The residue was purified by silica chromatography to provide 15A (2.70 g, 5.53 mmol, 78% yield) as a white foam. LC-MS Anal. Calc'd for C₂₈H₃₀FNO₄: 463.54. found [M+H] 464.3. ¹H NMR (500 MHz, CDCl₃) δ 7.37-7.28 (m, 2H), 7.15 (d, J=8.0 Hz, 1H), 7.07-7.02 (m, 3H), 6.93 (dd, J=6.3, 3.0 Hz, 1H), 6.80 (dt, J=8.9, 3.5 Hz, 1H), 6.59 (d, J=8.5 Hz, 2H), 4.09-4.00 (m, 3H), 3.99-3.94 (m, 2H), 3.92 (s, 2H), 3.87 (dt, J=11.3, 5.7 Hz, 1H), 3.82 (s, 3H), 3.78-3.71 (m, 1H), 3.55 (d, J=9.9 Hz, 1H), 3.37 (d, J=10.2 Hz, 1H), 2.38-2.29 (m, 4H), 2.26-2.18 (m, 1H).

15B. (R)-8-((Benzyloxy)methyl)-7-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-1,4-dioxa-7-azaspiro[4.4]nonane: To a solution of 15A (0.500 g, 1.08 mmol) and benzyl bromide (0.15 mL, 1.3 mmol) in CH₂Cl₂ (5.4 mL) was added Ag₂O (0.375 g, 1.62 mmol). The mixture was stirred at rt under argon for 6 h. THF (6 mL) was added. The reaction mixture was cooled to 0° C. and 95% NaH (60 mg) was added. The reaction mixture was warmed to rt for 10 min and additional BnBr (0.15 mL, 1.3 mmol) was added. The reaction mixture was stirred at rt overnight, filtered though a pad of CELITE®, and rinsed with Et₂O. The reaction mixture was diluted with EtOAc (10 mL), washed with sat. aq. NH₄Cl (3×6 mL), dried (Na₂SO₄), and concentrated. The residue was purified by silica chromatography to provide 15B (0.503 g, 0.908 mmol, 84% yield) as a colorless oil. LC-MS Anal. Calc'd for C₃₅H₃₆FNO₄: 553.66. found [M+H] 554.4. ¹H NMR (400 MHz, CDCl₃) δ 7.37-7.22 (m, 7H), 7.14 (d, J=7.7 Hz, 1H), 7.07-6.96 (m, 3H), 6.93 (dd, J=6.3, 3.0 Hz, 1H), 6.77 (dt, J=8.8, 3.3 Hz, 1H), 6.50 (d, J=8.8 Hz, 2H), 4.52 (s, 2H), 4.07-4.01 (m, 1H), 3.99-3.85 (m, 6H), 3.78 (s, 3H), 3.75-3.66 (m, 1H), 3.59-3.48 (m, 1H), 3.46-3.40 (m, 1H), 3.38-3.28 (m, 1H), 2.35-2.18 (m, 5H).

15C. (R)-5-((Benzyloxy)methyl)-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)pyrrolidin-3-one: A solution of 15B (503 mg, 0.908 mmol) and TsOH (173 mg, 0.908 mmol) in acetone (12.7 mL) and water (5.4 mL) was heated to 56° C. for 12 h. Additional 10 mL of acetone-water was added and the temperature was raised to 70° C. The reaction mixture was stirred for 48 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with sat. aq. NaHCO₃. The aqueous layer was back extracted with EtOAc. The combined organic layers were dried (Na₂SO₄), filtered, and concentrated. The residue was purified silica chromatography to provide 15C (0.411 g, 0.806 mmol, 89% yield). LC-MS Anal. Calc'd for C₃₃H₃₂FNO₃: 509.61. found [M+H] 510.4. ¹H NMR (500 MHz, CDCl₃) δ 7.39-7.22 (m, 5H), 7.16 (d, J=7.7 Hz, 3H), 7.12-7.01 (m, 3H), 6.94 (dd, J=6.3, 3.3 Hz, 1H), 6.81 (dt, J=8.9, 3.5 Hz, 1H), 6.56 (d, J=8.5 Hz, 2H), 4.51-4.34 (m, 3H), 3.94 (s, 2H), 3.82 (s, 3H), 3.79-3.69 (m, 3H), 3.51 (dd, J=9.4, 2.2 Hz, 1H), 2.82 (dd, J=17.9, 9.1 Hz, 1H), 2.62 (d, J=17.9 Hz, 1H), 2.33 (s, 3H).

15D. (5R)-5-((Benzyloxy)methyl)-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-3-(2-methoxyphenyl)pyrrolidin-3-ol: To a suspension of cerium(III) chloride (32.8 mg, 0.133 mmol) and 15C (68 mg, 0.13 mmol) in THF (1.3 mL) at −70° C. was added a 1 M solution of (2-methoxyphenyl)magnesium bromide in THF (27 μL, 0.27 mmol) dropwise. The mixture was gradually warmed to rt over 2 h. The reaction mixture was recooled to −70° C. and addition 1 M (2-methoxyphenyl)magnesium bromide in THF (0.26 mL, 0.26 mmol) was added. The reaction mixture was gradually warmed to rt overnight. The reaction was quenched with sat. aq. NH₄Cl (3 mL). The product was extracted with EtOAc (3×2 mL) and the combined organic layers were dried (MgSO₄) and concentrated to give 15D. (51 mg, 0.082 mmol, 62% yield), which was used without further purification. LC-MS Anal. Calc'd for C₃₃H₃₂FNO₃: 509.61. found [M+H] 510.4.

15E. (2R)-2-((Benzyloxy)methyl)-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl)phenyl)-4-(2-methoxyphenyl)pyrrolidine: To a solution of 15D (110 mg, 0.178 mmol) in dichloroethane (0.89 mL) was added triethylsilane (0.43 mL, 2.7 mmol) followed by TFA (0.21 μL, 2.7 mmol). The mixture was stirred at 75° C. The solvent was evaporated and the residue was purified by silica chromatography to give 15E (73 mg, 0.12 mmol, 68% yield) as a white solid. LC-MS Anal. Calc'd for C₄₀H₄₀FNO₃: 601.75. found [M+H] 602.5.

15F. ((2R)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl) phenyl)-4-(2-methoxyphenyl)pyrrolidin-2-yl)methanol: To a solution of 15E (60 mg, 0.10 mmol) and ammonium formate (126 mg, 1.99 mmol) in MeOH (2 mL) was added 10% Pd/C (53 mg, 0.050 mmol). The reaction mixture was heated to reflux overnight. The reaction mixture was filtered though a pad of CELITE® and rinsed with MeOH/CH₂Cl₂ (1:1 v/v). The reaction mixture was concentrated to give 15F (48 mg, 0.094 mmol, 95% yield) as a colorless oil, which was used without further purification. LC-MS Anal. Calc'd for C₃₃H₃₄FNO₃: 511.63. found [M+H] 512.4.

Example 15, Isomer 1 and Isomer 2 were prepared as single isomers following the procedure of Example 1 followed by chiral SFC separation. Example 15, Isomer 1 (white solid, 6.9 mg). LC-MS Anal. Calc'd for C₃₄H₃₄FNO₄: 539.64. found [M+H] 540.4. ¹H NMR (500 MHz, methanol-d₄) δ 7.48 (d, J=7.4 Hz, 2H), 7.40-7.26 (m, 6H), 7.23 (d, J=7.7 Hz, 1H), 7.08 (dd, J=10.3, 8.9 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H), 6.99-6.92 (m, 2H), 6.88 (dt, J=8.9, 3.5 Hz, 1H), 4.48 (dq, J=11.5, 5.6 Hz, 1H), 4.17-4.08 (m, 3H), 4.08-4.02 (m, 1H), 4.01-3.94 (m, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 2.86-2.75 (m, 2H), 2.75-2.66 (m, 1H), 2.40-2.31 (m, 1H), 2.29 (s, 3H). Analytical HPLC: RT=10.0 min, HI: 99.0%. hGPR40 EC₅₀=39 nM. Example 15, Isomer 2 (white solid, 9.9 mg). LC-MS Anal. Calc'd for C₃₄H₃₄FNO₄: 539.64. found [M+H] 540.4. ¹H NMR (500 MHz, methanol-d₄) δ 7.42-7.26 (m, 8H), 7.21 (d, J=7.7 Hz, 1H), 7.06 (td, J=10.0, 8.8 Hz, 2H), 6.99-6.92 (m, 2H), 6.87 (dt, J=8.9, 3.5 Hz, 1H), 4.58-4.47 (m, 1H), 4.08 (s, 2H), 4.07-3.95 (m, 2H), 3.92 (s, 3H), 3.80 (s, 3H), 3.77-3.68 (m, 1H), 2.81 (dd, J=16.8, 4.4 Hz, 1H), 2.70 (dd, J=16.2, 8.0 Hz, 2H), 2.38 (ddd, J=13.2, 9.1, 7.4 Hz, 1H), 2.27 (s, 3H). Analytical HPLC: RT=11.4 min, HI: 99.0%. hGPR40 EC₅₀=61 nM.

Example 16 2-((2R,4S)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methoxy)phenyl)-4-phenylpyrrolidin-2-yl)acetic acid, HCl

16A. 2-((2R,4S)-1-(4-(Benzyloxy)phenyl)-4-phenylpyrrolidin-2-yl)acetic acid, HCl: 16A was prepared from 4-benzyloxyiodobenzene and 1C following the procedure of Example 1. LC-MS Anal. Calc'd for C₂₅H₂₅NO₃: 387.47. found [M+H] 388.4. ¹H NMR (500 MHz, methanol-d₄) δ 7.62-7.55 (m, 2H), 7.47-7.41 (m, 4H), 7.41-7.35 (m, 4H), 7.34-7.27 (m, 2H), 7.19 (d, J=9.1 Hz, 2H), 5.15 (s, 2H), 4.46 (dd, J=5.6, 11.4 Hz, 1H), 4.13-3.97 (m, 3H), 2.94-2.85 (m, 1H), 2.82 (d, J=6.1 Hz, 2H), 2.33-2.16 (m, 1H).

16B. Methyl 2-((2R,4S)-1-(4-(benzyloxy)phenyl)-4-phenylpyrrolidin-2-yl)acetate: To a solution of 16A acid (260 mg, 0.671 mmol) in MeOH (2.9 mL) at −78° C. was added dropwise trimethylsilyldiazomethane (1.7 mL, 3.4 mmol). The reaction mixture was warmed to rt and stirred for 5 h. The reaction mixture was concentrated and the residue was purified by silica chromatography to afford 16B (0.222 g, 0.553 mmol, 82% yield). ¹H NMR (500 MHz, CDCl₃) δ 7.46-7.39 (m, 2H), 7.39-7.34 (m, 2H), 7.33-7.28 (m, 4H), 7.28-7.20 (m, 2H), 6.96-6.89 (m, 2H), 6.66-6.58 (m, 2H), 5.00 (s, 2H), 4.26-4.16 (m, 1H), 3.71-3.62 (m, 4H), 3.55 (t, J=9.2 Hz, 1H), 3.45-3.34 (m, 1H), 3.02 (dd, J=3.0, 15.4 Hz, 1H), 2.78-2.70 (m, 1H), 2.22 (dd, J=9.8, 15.3 Hz, 1H), 2.03-1.95 (m, 1H).

16C. Methyl 2-((2R,4S)-1-(4-hydroxyphenyl)-4-phenylpyrrolidin-2-yl)acetate: To a degassed solution of 16B (0.222 g, 0.553 mmol) in EtOAc (5.5 mL) was added 10% Pd/C (0.059 g, 0.055 mmol). The reaction vessel was charged with H₂ (1 atm) and stirred at rt overnight. Additional 10% Pd/C (60 mg) was added. EtOH (5 mL) was added. The reaction vessel was charged with H₂ (1 atm) and stirred at rt overnight. The reaction mixture was filtered through a pad of CELITE® and rinsed with EtOH. The solvent was removed to provide 16C (120 mg, 0.385 mmol, 70% yield) as a light orange oil. LC-MS Anal. Calc'd for C₁₉H₂₁NO₃: 311.38. found [M+H] 312.2.

16D. 2′-Fluoro-5′-methoxy-3-methylbiphenyl-4-carboxylic acid: 2-Fluoro-5-methoxyphenylboronic acid (1.04 g, 6.14 mmol), 4-bromo-2-methylbenzoic acid (1.2 g, 5.6 mmol), TBAB (1.80 g, 5.58 mmol), Pd(Ph₃P)₄ (0.129 g, 0.112 mmol), and Na₂CO₃ (2.37 g, 22.3 mmol) were combined in a microwave tube and degassed water (11.2 mL) was added. The vial was sealed and microwaved at 130° C. for 20 min. The reaction mixture was diluted with EtOAc/water and acidified to pH 1 with 1 N aq. HCl. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried (MgSO₄) and concentrated to give 16D (1.33 g, 5.11 mmol, 92% yield) as a pale yellow solid, which was used without further purification. LC-MS Anal. Calc'd for C₁₅H₁₃FO₃: 260.26. found [M+H] 261.0. ¹H NMR (500 MHz, CDCl₃) δ 12.28 (1H, br s), 8.16 (1H, d, J=8.53 Hz), 7.42-7.53 (2H, m), 7.09 (1H, t, J=9.35 Hz), 6.97 (1H, dd, J=6.19, 3.16 Hz), 6.88 (1H, dt, J=9.01, 3.34 Hz), 3.84 (3H, s), 2.74 (3H, s).

16E. (2′-Fluoro-5′-methoxy-3-methylbiphenyl-4-yl)methanol: 16D (3.066 g, 11.78 mmol) was dissolved in THF (50 mL) and cooled to 0° C. LAH (0.984 g, 25.9 mmol) was added in several portions. The reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was recooled to 0° C. and quenched by the addition of 0.98 mL water, 0.98 mL 15% aq. NaOH, and 2.9 mL water. The reaction mixture was warmed to rt and stirred for 30 min. The solids were filtered off and the organic layer was dried (MgSO₄) and concentrated. The crude product was purified by silica chromatography afford 16E (2.57 g, 10.4 mmol, 89% yield) as a colorless oil. LC-MS Anal. Calc'd for C₁₅H₁₅FO₂ 246.28. found [M-OH] 229.0. ¹H NMR (500 MHz, CDCl₃) δ 7.42-7.46 (1H, m, J=7.70 Hz), 7.35-7.41 (2H, m), 7.07 (1H, dd, J=9.90, 9.08 Hz), 6.94 (1H, dd, J=6.33, 3.03 Hz), 6.83 (1H, ddd, J=8.94, 3.58, 3.44 Hz), 4.74 (2H, s), 3.82 (3H, s), 2.41 (3H, s), 1.80 (1H, s).

16F. 4′-(Bromomethyl)-2-fluoro-5-methoxy-3′-methylbiphenyl: Lithium bromide (1.06 g, 12.2 mmol) was added to dry THF (12.2 mL) and the reaction mixture was stirred for 10 min until the solids dissolved. The solution was cannulated into a flask containing 16E (0.300 g, 1.22 mmol) and NEt₃ (0.85 mL, 6.1 mmol) was added. The reaction mixture was cooled to 0° C. and MsCl (0.24 mL, 3.1 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1.5 h. The reaction mixture was diluted with hexanes and washed with water and brine. The organic layer was dried (MgSO₄) and concentrated. The crude product was purified by silica chromatography to afford 16F (0.333 g, 1.08 mmol, 89% yield) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.32-7.43 (3H, m), 7.06 (1H, dd, J=9.85, 9.09 Hz), 6.93 (1H, dd, J=6.32, 3.03 Hz), 6.83 (1H, dt, J=8.84, 3.41 Hz), 4.57 (2H, s), 3.82 (3H, s), 2.48 (3H, s).

16G. Methyl 2-((2R,4S)-1-(4-((2′-fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methoxy)phenyl)-4-phenylpyrrolidin-2-yl)acetate: A mixture of 16C (24 mg, 0.077 mmol), 16F (28.6 mg, 0.092 mmol), and K₂CO₃ (21.3 mg, 0.154 mmol) in CH₃CN (0.77 mL) was stirred at 86° C. for 10 h. The reaction mixture was diluted with water (1 mL) and extracted with EtOAc (3×1 mL). The combined organic layers were dried (MgSO₄) and concentrated. The crude product was purified by silica chromatography to provide 16G (11 mg, 0.020 mmol, 26% yield) as a colorless oil. LC-MS Anal. Calc'd for C₃₄H₃₄FNO₄: 539.64. found [M+H] 540.2.

Example 16

A solution of 16G (11 mg, 0.020 mmol) and LiOH (0.976 mg, 0.041 mmol) in THF (136 μl) and water (67.9 μl) was stirred at rt overnight. The reaction mixture was acidified with 1 N aq. HCl and extracted with EtOAc (3×2 mL). The combined organic layers were concentrated. The crude product was purified by RP-Prep. HPLC. The residue was dissolved in CH₃CN and several mL of 3 N aq. HCl were added. The reaction mixture was concentrated and the procedure was repeated 2×. The aqueous layer was lyophilized overnight to give Example 16 (7.0 mg, 0.012 mmol, 61% yield) as white solid. LC-MS Anal. Calc'd for C₃₃H₃₂FNO₄: 525.61. found [M+H] 526.3. ¹H NMR (500 MHz, methanol-d₄) δ 7.60 (br. s., 2H), 7.50-7.34 (m, 7H), 7.32-7.27 (m, 1H), 7.23 (d, J=9.1 Hz, 2H), 7.09 (dd, J=10.0, 8.9 Hz, 1H), 6.97 (dd, J=6.3, 3.0 Hz, 1H), 6.90 (dt, J=9.1, 3.4 Hz, 1H), 5.20 (br. s., 2H), 4.48 (br. s., 1H), 4.18-3.97 (m, 3H), 3.81 (s, 3H), 2.96-2.87 (m, 1H), 2.87-2.76 (m, 2H), 2.44 (s, 3H), 2.25 (q, J=11.6 Hz, 1H). Analytical HPLC: RT=9.5 min, HI: 99.0%. hGPR40 EC₅₀=1000 nM.

Example 17 2-((2S,3S,4R)-1-(4-((2′-Fluoro-5′-methoxy-3-methyl-[1,1′-biphenyl]-4-yl)methyl) phenyl)-4-(3-methoxypropoxy)-3-methylpyrrolidin-2-yl)acetic acid, HCl

17A. (R)-1-Benzyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)-4,5-dihydro-1H-pyrrole-1,2-dicarboxylate: To a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate, HCl (10.0 g, 55.3 mmol) in CH₂Cl₂ (76 mL) at rt was added imidazole (8.66 g, 127 mmol) and TBS-Cl (9.17 g, 60.8 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was washed with 10% aq. Na₂CO₃ (75 mL). The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (75 mL). The combined organic layers were concentrated to a small volume and then toluene was added and the fractions were concentrated to ˜75 mL. The toluene phase was washed with water and then used directly in the next step. To the solution of (2S,4R)-methyl 4-((tert-butyldimethylsilyl)oxy)pyrrolidine-2-carboxylate in toluene cooled to 0° C. was added water (25 mL) followed by NaDCC (6.69 g, 30.4 mmol). After 30 min, the reaction mixture was filtered through CELITE®, washed with toluene (30 mL), and the phases were separated. The organic phase was washed with water, cooled to 0° C., and NEt₃ (9.3 mL, 66 mmol) was added. The reaction mixture was stirred for 1 h at 0° C. and then overnight at rt. The organic solution was washed with water (2×), dried (MgSO₄), and concentrated. The crude material was used directly in the next step without further purification. To a solution of (R)-methyl 3-((tert-butyldimethylsilyl)oxy)-3,4-dihydro-2H-pyrrole-5-carboxylate in CH₂Cl₂ (101 mL) at −10° C. was added 2,6-lutidine (11.8 mL, 101 mmol) followed by the dropwise addition of benzyl chloroformate (7.9 mL, 56 mmol) and the reaction mixture was warmed to rt and stirred overnight. Ethylenediamine (0.50 mL, 7.4 mmol) was added to the reaction mixture, which was stirred for 15 min at rt and then washed with 1 N aq. citric acid (60 mL) and 1 N aq. HCl (50 mL). The organic layer was washed with water, 1.5 N aq. KH₂PO₄, and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by silica chromatography to provide 17A (16.3 g, 41.6 mmol, 82% yield) as a colorless oil. LC-MS Anal. Calc'd for C₂₀H₂₉NO₅Si: 391.55. found [M+H] 392.0. ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.29 (m, 5H), 5.69-5.62 (m, 1H), 5.20-5.11 (m, 2H), 4.94 (dt, J=7.7, 3.2 Hz, 1H), 3.98 (dd, J=12.4, 8.0 Hz, 1H), 3.79 (dd, J=12.2, 3.4 Hz, 1H), 3.71-3.62 (m, 3H), 0.88 (s, 9H), 0.07 (d, J=3.3 Hz, 6H).

17B. (2R,3S,4R)-1-Benzyl 2-methyl 4-((tert-butyldimethylsilyl)oxy)-3-methylpyrrolidine-1,2-dicarboxylate: CuBr.SMe₂ (4.78 g, 23.2 mmol) was suspended in anhydrous Et₂O (51 mL) and cooled to −40° C. A 1.6 M solution of MeLi in Et₂O (29.1 mL, 46.5 mmol) was added dropwise via addition funnel. The solution was stirred for 1 h and then a solution of 17A (7.00 g, 17.9 mmol) in Et₂O (20.4 mL) was added dropwise via addition funnel. The reaction mixture was stirred for 45 min at −45° C. and then transferred via cannula to a vigorously stirred solution of sat. aq. NH₄Cl and stirred for 30 min. The organic layer was separated and washed with sat. aq. NH₄Cl. The combined aqueous layers were extracted with hexanes. The combined organic layers were dried (MgSO₄) and concentrated. The crude material was purified by silica chromatography to obtain 17B (5.11 g, 12.5 mmol, 70% yield) as a colorless oil. LC-MS Anal. Calc'd for C₂₁H₃₃NO₅Si: 407.58. found [M+H] 408.2. ¹H NMR (500 MHz, CDCl₃) δ (two rotamers) 7.40-7.27 (m, 5H), 5.21-5.00 (m, 2H), 4.01-3.90 (m, 1H), 3.87-3.80 (m, 1.6H), 3.77-3.71 (s and m, 1.8H), 3.57 (s, 1.6H), 3.36-3.28 (m, 1H), 2.33-2.25 (m, 1H), 1.11 (dd, J=7.2, 2.2 Hz, 3H), 0.86 (s, 9H), 0.08-0.01 (m, 6H).

17C. (2R,3S,4R)-1-Benzyl 2-methyl 4-hydroxy-3-methylpyrrolidine-1,2-dicarboxylate: To a solution of 17B (5.10 g, 12.5 mmol) in THF (42 mL) was added a 1 M solution of TBAF in THF (19 mL, 19 mmol) and the reaction mixture was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc and washed with water and brine, dried (MgSO₄), and concentrated. The crude material was purified by silica chromatography to obtain 17C (3.61 g, 12.3 mmol, 98% yield) as a colorless oil, which crystallized to a white solid upon standing. LC-MS Anal. Calc'd for C₁₅H₁₉NO₅: 293.32. found [M+H] 294.0. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.27 (m, 5H), 5.25-4.97 (m, 2H), 4.09-3.96 (m, 1H), 3.95-3.87 (m, 1H), 3.86-3.70 (m, 3H), 3.69-3.57 (m, 2H), 3.10-2.83 (m, 1H), 2.37 (td, J=6.9, 2.9 Hz, 1H), 1.12 (d, J=7.3 Hz, 3H).

17D. (2R,3S,4R)-1-Benzyl 2-methyl 4-(allyloxy)-3-methylpyrrolidine-1,2-dicarboxylate: To a solution of 17C (0.405 g, 1.38 mmol) in DMF (6.9 mL) at 0° C. was added 60% NaH (0.083 g, 2.1 mmol). The reaction mixture was stirred for 30 min and then allyl bromide (0.18 mL, 2.1 mmol) was added. The reaction mixture was warmed to rt and stirred for 1 h. The reaction mixture was quenched with water and diluted with EtOAc. The layers were separated and the organic layer was washed with water (4×). The organic layer was washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to provide 17D (0.446 g, 1.34 mmol, 97% yield) as a colorless oil. LC-MS Anal. Calc'd for C₁₈H₂₃NO₅: 333.38. found [M+H] 334.0. ¹H NMR (500 MHz, CDCl₃) δ (two rotamers) 7.41-7.27 (m, 5H), 5.90-5.77 (m, 1H), 5.29-4.99 (m, 4H), 4.09-3.90 (m, 3H), 3.86 and 3.80 (2 dd, J=11.3, 5.6 Hz, 1H), 3.73 and 3.57 (2 s, 3H), 3.67-3.61 (m, 1H), 3.46 (ddd, J=11.0, 6.1, 4.7 Hz, 1H), 2.59-2.44 (m, 1H), 1.14 (dd, J=7.2, 1.1 Hz, 3H).

17E. (2R,3S,4R)-1-Benzyl 2-methyl 4-(3-hydroxypropoxy)-3-methylpyrrolidine-1,2-dicarboxylate: To a solution of 17D (2.74 g, 8.20 mmol) in THF (4.1 mL) at 0° C. was added a 1 M solution of BH₃.THF (2.8 mL, 2.8 mmol) in THF. After 15 min, the reaction mixture was stirred at rt for 2.2 h. Additional BH₃.THF (1 M in THF) (0.2 mL, 0.2 mmol) was added and the reaction mixture was stirred for an additional 15 min. Water (4.1 mL) and sodium perborate.4H₂O (1.29 g, 8.37 mmol) were added. After stirring for 2 h, the reaction mixture was diluted with EtOAc, washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to provide 17E (2.17 g, 6.18 mmol, 75% yield) as a colorless oil. LC-MS Anal. Calc'd for C₁₈H₂₅NO₆: 351.39. found [M+H] 352.0. ¹H NMR (500 MHz, CDCl₃) δ (two rotamers) 7.43-7.27 (m, 5H), 5.26-5.00 (m, 2H), 4.18-3.98 (m, 1H), 3.84-3.76 (m, 1H), 3.75 and 3.61 (two s, 3H), 3.73-3.66 (m, 2H), 3.61-3.50 (m, 4H), 2.62-2.50 (m, 1H), 2.04-2.00 (m, 1H), 1.77 (quind, J=5.7, 2.9 Hz, 2H), 1.12 (d, J=7.2 Hz, 3H).

17F. (2R,3S,4R)-1-Benzyl 2-methyl 4-(3-methoxypropoxy)-3-methylpyrrolidine-1,2-dicarboxylate: To a solution of 17E (2.17 g, 6.18 mmol) in MeCN (7.7 mL) was added Ag₂O (3.58 g, 15.4 mmol) and MeI (3.9 mL, 62 mmol). The reaction mixture was stirred at 50° C. for 18 h. The mixture was filtered and concentrated. The crude product was purified by silica chromatography to provide 17F (2.71 g, 7.42 mmol, 81% yield). LC-MS Anal. Calc'd for C₁₉H₂₇NO₆: 365.42. found [M+H] 367.0. ¹H NMR (500 MHz, CDCl₃) δ 7.41-7.27 (m, 5H), 5.24-4.99 (m, 2H), 4.08-3.94 (m, 1H), 3.89-3.76 (m, 1H), 3.73, 3.58 (2 s, 3H), 3.57-3.53 (m, 1H), 3.51-3.42 (m, 3H), 3.40 (t, J=6.2 Hz, 2H), 3.32, 3.3 (2 s, 3H), 2.49 (dtd, J=6.9, 4.7, 2.2 Hz, 1H), 1.76 (quind, J=6.3, 2.1 Hz, 2H), 1.13 (dd, J=7.2, 3.0 Hz, 3H).

17G. (2R,3S,4R)-Benzyl 2-(hydroxymethyl)-4-(3-methoxypropoxy)-3-methylpyrrolidine-1-carboxylate: To a solution of 17F (4.13 g, 11.3 mmol) in THF (57 mL) at 0° C. was added a 2 M solution of LiBH₄ (11.3 mL, 22.6 mmol) in THF. The reaction mixture was warmed to rt and stirred for 17 h. The reaction mixture was cooled to 0° C., carefully quenched with sat. aq. NH₄Cl, and diluted with EtOAc/water. The layers were separated and the organic layer was washed with brine, dried (MgSO₄), and concentrated. The crude product was purified by silica chromatography to provide 17G (3.25 g, 9.15 mmol, 81%) as a colorless oil. LC-MS Anal. Calc'd for C₁₈H₂₇NO₅: 337.41. found [M+H] 338.0. ¹H NMR (500 MHz, CDCl₃) δ 7.40-7.28 (m, 5H), 5.14 (s, 2H), 4.41-4.31 (m, 1H), 3.85-3.70 (m, 3H), 3.69-3.61 (m, 1H), 3.57-3.47 (m, 3H), 3.46-3.39 (m, 2H), 3.34-3.26 (m, 3H), 2.06-1.94 (m, 1H), 1.81 (quin, J=6.4 Hz, 2H), 1.09 (dd, J=9.9, 7.2 Hz, 3H).

17H. ((2R,3S,4R)-4-(3-Methoxypropoxy)-3-methylpyrrolidin-2-yl)methanol: A mixture of 17G (3.25 g, 9.63 mmol) and Pd/C (0.820 g, 0.771 mmol) in MeOH (193 mL) was purged with argon (3×) and then H₂ (3×). The reaction mixture was stirred under H₂ (1 atm) at rt for 3.5 h. The mixture was filtered though CELITE® and concentrated to give 17H (2.03 g, 9.99 mmol, 100% yield). LC-MS Anal. Calc'd for C₁₀H₂₁NO₃: 203.28. found [M+H] 204.1. ¹H NMR (500 MHz, CDCl₃) δ 3.63 (dd, J=11.1, 3.4 Hz, 1H), 3.55-3.49 (m, 2H), 3.47 (t, J=6.3 Hz, 2H), 3.43 (td, J=6.3, 2.1 Hz, 2H), 3.31 (s, 3H), 3.06-3.00 (m, 1H), 2.98-2.90 (m, 1H), 2.85-2.76 (m, 1H), 1.85 (dt, J=6.9, 3.4 Hz, 1H), 1.83-1.75 (m, 2H), 1.05 (d, J=7.2 Hz, 3H).

Example 17 was prepared from 17H following the procedure of Example 1. LC-MS Anal. Calc'd for C₃₂H₃₈FNO₅: 535.65. found [M+H] 536.3. ¹H NMR (500 MHz, acetonitrile-d₃) δ 7.72-7.59 (m, 2H), 7.39 (s, 1H), 7.35 (s, 1H), 7.31 (dd, J=8.5, 2.2 Hz, 2H), 7.20 (d, J=7.7 Hz, 1H), 7.12 (dd, J=10.5, 9.1 Hz, 1H), 6.99 (dd, J=6.3, 3.3 Hz, 1H), 6.89 (dt, J=8.9, 3.5 Hz, 1H), 4.06 (s, 2H), 4.04-3.97 (m, 1H), 3.92-3.84 (m, 1H), 3.80 (s, 3H), 3.79-3.75 (m, 1H), 3.75-3.67 (m, 1H), 3.57-3.51 (m, 2H), 3.43 (t, J=6.3 Hz, 2H), 3.27 (s, 3H), 3.02 (dt, J=17.3, 4.3 Hz, 1H), 2.79 (ddd, J=17.2, 5.9, 2.5 Hz, 1H), 2.47-2.37 (m, 1H), 2.29 (s, 3H), 1.78 (quin, J=6.3 Hz, 2H), 1.18 (dd, J=6.9, 2.2 Hz, 3H). Analytical HPLC: RT=13.1 min, HI: 96.0%. hGPR40 EC₅₀=39 nM. 

1. A compound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein: ring A is independently

ring B is independently a 6-membered aryl or 5- to 6-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, O, and S; and ring B is substituted with 0-4 R²; R¹ is independently phenyl, benzyl, naphthyl or a 5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said phenyl, benzyl, naphthyl and heteroaryl are each substituted with 0-3 R⁶; R², at each occurrence, is independently selected from: ═O, OH, halogen, C₁₋₆ alkyl substituted with 0-1 R¹², C₁₋₆ alkoxy substituted with 0-1 R¹², C₁₋₄ haloalkyl substituted with 0-1 R¹², C₁₋₄ haloalkoxy substituted with 0-1 R¹², —(CH₂)_(m)—C₃₋₆ carbocycle substituted with 0-1 R¹², and —(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S); wherein said heteroaryl is substituted with 0-1 R¹²; R³ is independently selected from: CN, C₁₋₆ alkyl substituted with 1 R¹⁰, C₁₋₆ alkoxy substituted with 1 R¹⁰, C₂₋₆ alkenyl substituted with 0-1 R¹⁰, C₂₋₆ alkynyl substituted with 0-1 R¹⁰, C₁₋₆ haloalkyl substituted with 1 R¹⁰, —(O)_(n)—(CH₂)_(m)—(C3-6 carbocycle substituted with 0-2 R¹⁰), —(O)_(n)—(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said heteroaryl is substituted with 0-2 R¹⁰); R⁴ and R^(4a) are independently selected from: H, halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, and —(CH₂)_(m)—C₃₋₆ carbocycle; R⁵, at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, and C₁₋₆ haloalkoxy; R⁶, at each occurrence, is independently selected from: halogen, OH, C₁₋₄ alkylthio, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₈ alkyl substituted with 0-1 R⁷, C₁₋₆ alkoxy substituted with 0-1 R⁷, —(O)_(n)—(CH₂)_(m)—(C₃₋₁₀ carbocycle substituted with 0-2 R⁷), and —(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S); wherein said heteroaryl is substituted with 0-2 R⁷; R⁷, at each occurrence, is independently selected from: halogen, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, SCF₃, CN, NO₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SO₂(C₁₋₂ alkyl), and phenyl; R⁸ is independently selected from: H and Cm alkyl; R¹⁰ and R¹², at each occurrence, is independently selected from: OH, halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), and tetrazolyl; R¹¹, at each occurrence, is independently selected from: H, C₁₋₄ alkyl and benzyl; m, at each occurrence, is independently 0, 1, or 2; and n, at each occurrence, is independently 0 or
 1. 2. A compound of Formula (I) according to claim 1, wherein R⁴ is hydrogen and R⁸ is hydrogen, further characterized by Formula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein: ring A is independently

ring B is independently

R¹ is independently phenyl, benzyl, naphthyl or a 5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said phenyl, benzyl, naphthyl and heteroaryl are each substituted with 0-3 R⁶; R², at each occurrence, is independently selected from: ═O, OH, halogen, C₁₋₆ alkyl substituted with 0-1 R¹², C₁₋₆ alkoxy substituted with 0-1 R¹², C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and benzyl; R³ is independently selected from: CN, C₁₋₆ alkyl substituted with 1 R¹⁰, C₁₋₆ alkoxy substituted with 1 R¹⁰, —(O)_(n)—(CH₂)_(m)—(C₃₋₆ cycloalkyl substituted with 0-2 R¹⁰), —(O)_(n)—(CH₂)_(m)-(phenyl substituted with 0-2 R¹⁰), and —(O)_(n)—(CH₂)_(m)-(a 5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said heteroaryl is substituted with 0-2 R¹⁰); R^(4a) is independently selected from: H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, and —(CH₂)_(m)—C₃₋₆ carbocycle; R⁵, at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy; R⁶, at each occurrence, is independently selected from: halogen, OH, C₁₋₄ alkylthio, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₁₋₈ alkyl substituted with 0-1 R⁷, C₁₋₄ alkoxy substituted with 0-1 R⁷, —(O)_(n)—(CH₂)_(m)—(C₃₋₆ carbocycle substituted with 0-2 R⁷), —(CH₂)_(m)-(naphthyl substituted with 0-2 R⁷), and —(CH₂)_(m)-(5- to 10-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said heteroaryl is substituted with 0-2 R⁷); R⁷, at each occurrence, is independently selected from: halogen, OH, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, SCF₃, CN, NO₂, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, SO₂(C₁₋₂ alkyl), and phenyl; R¹⁰ and R¹², at each occurrence, are independently selected from: OH, halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CO₂(C₁₋₄ alkyl), SO₂(C₁₋₄ alkyl), and tetrazolyl; R¹¹, at each occurrence, is independently selected from: H, C₁₋₄ alkyl and benzyl; m, at each occurrence, is independently 0, 1, or 2; and n, at each occurrence, is independently 0 or
 1. 3. A compound of Formula (I) or (II) according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein: ring A is independently

R¹ is independently phenyl substituted with 0-3 R⁶ or a heteroaryl substituted with 0-2 R⁶; wherein said heteroaryl is selected from: furanyl, oxazolyl, thiazolyl, pyrazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl; R², at each occurrence, is independently selected from: OH, halogen, C₁₋₄ alkyl substituted with 0-1 R¹², C₁₋₄ alkoxy substituted with 0-1 R¹², and benzyl; R^(4a) is independently selected from: H, halogen C₁₋₄ alkyl, C₁₋₄ alkoxy, and C₃₋₆ cycloalkyl; R⁶, at each occurrence, is independently selected from: halogen, OH, C₁₋₈ alkyl substituted with 0-1 OH, C₁₋₄ alkoxy, C₁₋₄ alkylthio, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, CN, SO₂(C₁₋₂ alkyl), N(C₁₋₄ alkyl)₂, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄ alkyl, C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl, —O—C₃₋₆ cycloalkyl, benzyl, and oxazolyl; and R¹⁰ and R¹², at each occurrence, are independently selected from: halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, SO₂(C₁₋₄ alkyl), and CO₂(C₁₋₂ alkyl), and tetrazolyl.
 4. A compound of Formula (I) or (II) according to claim 3, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein: R¹ is independently phenyl substituted with 0-3 R⁶ or a heteroaryl substituted with 0-2 R⁶; wherein said heteroaryl is selected from: thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl.
 5. A compound of Formula (I) according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein: R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶, pyridinyl substituted with 0-2 R⁶, pyrazinyl substituted with 0-2 R⁶, pyrimidinyl substituted with 0-2 R⁶, or thiazolyl substituted with 0-2 R⁶; R², at each occurrence, is independently selected from: OH, halogen, C₁₋₆ alkyl substituted with 0-1 CN, C₁₋₆ alkoxy, benzyl, and tetrazolylmethyl; R⁶, at each occurrence, is independently selected from: halogen, CN, C₁₋₈ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄ alkyl, C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl, —O—C₃₋₆ cycloalkyl, benzyl, and oxazolyl; and R¹⁰, at each occurrence, is independently selected from: halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, and CO₂(C₁₋₂ alkyl).
 6. A compound of Formula (I) according to claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein: R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶ or pyridinyl substituted with 0-2 R⁶; R², at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, and C₁₋₆ alkoxy; R³ is independently selected from: CN, C₁₋₆ alkyl substituted with 1 R¹⁰, C₁₋₆ alkoxy substituted with 1 R¹⁰, —(O)_(n)—(CH₂)_(m)—(C₃₋₆ cycloalkyl substituted with 0-1 R¹⁰), —(O)_(n)—(CH₂)_(m)-(phenyl substituted with 0-2 R¹⁰), and —(O)_(n)—(CH₂)_(m)-(a 5- to 6-membered heteroaryl containing carbon atoms and 1-4 heteroatoms selected from N, NR¹¹, O, and S; wherein said heteroaryl is substituted with 0-1 R¹⁰); R⁶, at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄ alkyl, C₅₋₆ cycloalkenyl substituted with 0-2 C₁₀₄ alkyl, and benzyl; and R¹⁰, at each occurrence, is independently selected from: halogen, CN, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₀₄ haloalkyl, and C₁₋₄ haloalkoxy.
 7. A compound of Formula (III) or (Ma):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein: R¹, at each occurrence, is independently phenyl substituted with 0-3 R⁶ or pyridinyl substituted with 0-2 R⁶; R², at each occurrence, is independently selected from: halogen, C₁₋₄ alkyl, and C₁₋₆ alkoxy; R³, at each occurrence, is independently selected from: CN, C₁₋₄ alkoxy substituted with 1 R¹⁰, —(CH₂)_(m)—(C₃₋₆ cycloalkyl substituted with 0-2 R¹⁰), —(CH₂)_(m)-(phenyl substituted with 0-1) (CH₂)_(m)-(pyridinyl substituted with 0-1 R¹⁰), and —(CH₂)_(m)-(isoxazolyl substituted with 0-1 R¹⁰); R^(4a), at each occurrence, is independently selected from: H, halogen, C₁₋₄ alkyl, C₁₋₄ alkoxy, and cyclopropyl; R⁵, at each occurrence, is independently halogen and C₁₋₆ alkoxy; R⁶, at each occurrence, is independently selected from: halogen, C₁₋₆ alkyl, C₁₋₄ alkoxy, C₃₋₆ cycloalkyl substituted with 0-2 C₁₋₄ alkyl, and C₅₋₆ cycloalkenyl substituted with 0-2 C₁₋₄ alkyl; and R¹⁰ is independently selected from: halogen, CF₃, OCF₃, CN, C₁₋₄ alkyl, and C₁₋₄ alkoxy.
 8. A compound according to claim 7 with Formula (IV) or (IVa):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
 9. A compound of Formula (IV) or (IVa) according to claim 8, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein: R¹ is independently phenyl substituted with 0-3 R⁶ or pyridinyl substituted with 0-2 R⁶; R² is independently halogen or C₁₋₄ alkyl; R³ is independently selected from: CN, cyclohexyl, C₁₋₄ alkoxy substituted with 1 C₁₋₄ alkoxy, phenyl substituted with 0-1 R¹⁰, pyridinyl substituted with 0-1 R¹⁰, and isoxazolyl substituted with 0-1 R¹⁰; R^(4a) is independently selected from: H, halogen, C₁₋₄ alkyl, and C₁₋₄ alkoxy; R⁶, at each occurrence, is independently selected from: halogen, C₁₋₄ alkyl, and C₁₋₄ alkoxy; and R¹⁰, at each occurrence, is independently selected from: halogen, C₁₋₄ alkyl, and C₁₋₄ alkoxy.
 10. A compound according to claim 1, wherein the compound is selected from the exemplified examples or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
 11. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
 12. The pharmaceutical composition according to claim 11, further comprising one or more other suitable therapeutic agents selected from: anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-restenotic agents, anti-pancreatic agents, lipid lowering agents, anorectic agents, and appetite suppressants.
 13. (canceled)
 14. A compound of claim 1, or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, for use in treating diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetic kidney disease, acute kidney injury, cardiorenal syndrome, acute coronary syndrome, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, congestive heart failure, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, fatty liver disease, dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), non-cardiac ischemia, pancreatitis, lipid disorders, and liver diseases such as NASH (Non-Alcoholic SteatoHepatitis), NAFLD (Non-Alcoholic Fatty Liver Disease), liver cirrhosis, inflammatory bowel diseases incorporating ulcerative colitis and Crohn's disease, celiac disease, osteoarthritis, nephritis, psoriasis, atopic dermatitis, and skin inflammation.
 15. A compound for use according to claim 14, wherein the compound is used simultaneously, separately or sequentially with one or more additional therapeutic agents.
 16. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
 17. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.
 18. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.
 19. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.
 20. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.
 21. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.
 22. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.
 23. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.
 24. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof.
 25. A compound according claim 1, having the structure:

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof. 